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  • 1.
    Alim, Abdul
    et al.
    Uppsala University, Sweden; Karolinska Institute, Sweden; Uppsala University, Sweden.
    Ackermann, Paul W.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Blomgran, Parmis
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Kristiansson, Per
    Uppsala University, Sweden.
    Pejler, Gunnar
    Uppsala University, Sweden; Swedish University of Agriculture Science, Sweden.
    Peterson, Magnus
    Uppsala University, Sweden.
    Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture2017Inngår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, nr 3, s. 451-460Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

  • 2.
    Andersson, Therese
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Achilles tendon healing in rats is improved by intermittent mechanical loading during the inflammatory phase2012Inngår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 30, nr 2, s. 274-279Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tendons adapt to changes in mechanical loading, and numerous animal studiesshow that immobilization of a healing tendon is detrimental to the healingprocess. The present study addresses whether the effects of a few episodes ofmechanical loading are different during different phases of healing. Fifty femalerats underwent Achilles tendon transection, and their hind limbs were unloadedby tail suspension on the day after surgery. One group of 10 rats was taken downfrom suspension to walk on a treadmill for 30 minutes per day, on days 2-5 aftertransection. They were euthanized on day 8. Another group underwent similartreadmill running on days 8-11 and was euthanized on day 14. Completelyunloaded groups were euthanized on day 8 and 14. Tendon specimens were thenevaluated mechanically. The results showed that just 4 loading episodesincreased the strength of the healing tendon. This was evident irrespective of thetime-point when loading was applied (early or late). The positive effect on earlyhealing was unexpected, considering that the mechanical stimulation was appliedduring the inflammatory phase, when the calluses were small and fragile. Ahistological study of additional groups with early loading also showed someincreased bleeding in the loaded calluses. Our results indicate that a smallamount of early loading may improve the outcome of tendon healing. This couldbe of interest to clinical practice.

  • 3.
    Andersson, Therese
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Growth hormone does not stimulate early healing in rat tendons2012Inngår i: International Journal of Sports Medicine, ISSN 0172-4622, E-ISSN 1439-3964, Vol. 33, nr 3, s. 240-243Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Growth Hormone stimulates bone growth and fracture repair. It acts mainly by increasing the systemic levels of IGF-1. Local treatment with IGF-1 appears to stimulate tendon healing. We therefore hypothesized that systemic treatment with Growth Hormone would also stimulate tendon healing. Rat Achilles tendons were transected and left to heal. 4 groups were studied. Intramuscular injections of botulinum toxin A (Botox) were used to reduce loading in 2 groups. The animals were randomized to twice daily injections of Growth Hormone (n=2×10) or saline (n=2×10), and killed after 10 days. Healing was assessed by mechanical testing. Muscle paralysis induced by Botox reduced the strength of the healing tendon by two thirds. Growth Hormone increased femoral and tibial length in the unloaded, and femoral and tibial weight in the loaded group. Body weight and muscle weight were increased in both. In contrast, there was no increase in the strength of the healing tendons, regardless of mechanical loading status. An increase in peak force of the loaded healing tendons by more than 5% could be excluded with 95% confidence. In spite of its stimulatory effects on other tissues, Growth Hormone did not appear to stimulate tendon or tendon repair.

  • 4.
    Andersson, Therese
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Tissue memory in healing tendons: short loading episodes stimulate healing2009Inngår i: JOURNAL OF APPLIED PHYSIOLOGY, ISSN 8750-7587, Vol. 107, nr 2, s. 417-421Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Intact tendons adapt slowly to changes in mechanical loading, whereas in healing tendons the effect of mechanical loading or its absence is dramatic. The longevity of the response to a single loading episode is, however, unknown. We hypothesized that the tissue has a "memory" of loading episodes and that therefore short loadings are sufficient to elicit improved healing. The Achilles tendon of 70 female rats was transected and unloaded by tail suspension for 12 days (suspension started on day 2 after surgery). Each day, the rats were let down from suspension for short daily training episodes according to different regimes: 15 min of cage activity or treadmill running for 15, 30, 60, or 2 x 15 min. Rats with transected Achilles tendons and full-time cage activity served as controls. The results demonstrated that full-time cage activity increased the peak force over three times compared with unloading. Short daily loading episodes (treadmill running) increased the peak force about half as much as full-time activity. Prolongation of treadmill running above 15 min or dividing the daily training in two separate episodes had minimal further effect. This mechanical stimulation increased the cross-sectional area but had no effect on the mechanical properties of the repair tissue. The findings indicate that once the tissue had received information from a certain loading type and level, this is "memorized" and leads to a response lasting many hours. This suggests that patients might be allowed early short loading episodes following, e. g., an Achilles tendon rupture for a better outcome.

  • 5.
    Andersson, Therese
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Hammerman, Malin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Sandberg, Olof
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Low-level mechanical stimulation is sufficient to improve tendon healing in rats2012Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 113, nr 9, s. 1398-1402Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Treatment of tendon injuries often involves immobilization. However, immobilization might not prevent mild involuntary isometric muscle contraction. The effect of weak forces on tendon healing is therefore of clinical interest. Studies of tendon healing with various methods for load reduction in rat Achilles tendon models show a consistent reduction in tendon strength by at least half, compared with voluntary cage activity. Unloading was not complete in any of these models, and the healing tendon was therefore still exposed to mild mechanical stimulation. By reducing the forces acting on the tendon even further, we now studied the effects of this mild stimulation. Rat Achilles tendons were transected and allowed to heal spontaneously under four different loading conditions: 1) normal cage activity; 2) calf muscle paralysis induced by botulinum toxin A (Botox); 3) tail suspension; 4) Botox and tail suspension, combined, to eliminate even mild stimulation. Healing was evaluated by mechanical testing after 8 days. Botox alone and suspension alone both reduced tendon callus size (transverse area), thereby impairing its strength compared with normal cage activity. The combination of Botox and suspension did not further reduce tendon callus size but drastically impaired the material properties of the tendon callus compared with each treatment alone. The peak force was only a fifth of that in the normal cage activity group. The results indicate that also the mild loading that occurs with either Botox or suspension alone stimulates tendon healing. This stimulation appears to affect mainly tissue quality, whereas stronger stimulation also increases callus size.

  • 6.
    Bernhardsson, Magnus
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Dietrich, Franciele
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Tätting, Love
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Depletion of cytotoxic (CD8+) T cells impairs implant fixation in rat cancellous bone2019Inngår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 37, nr 4, s. 805-811Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    As cytotoxic (CD8(+)) T cells seem to impair shaft fracture healing, we hypothesized that depletion of CD8(+) cells would instead improve healing of cancellous bone. Additionally, we also tested if CD8-depletion would influence the healing of ruptured Achilles tendons. Rats received a single injection of either anti-CD8 antibodies or saline and put through surgery 24 h later. Three different surgical interventions were performed as follows: (1) a drill hole in the proximal tibia with microCT (BV/TV) to assess bone formation; (2) a screw in the proximal tibia with mechanical evaluation (pull-out force) to assess fracture healing; (3) Achilles tendon transection with mechanical evaluation (force-at-failure) to assess tendon healing. Furthermore, CD8-depletion was confirmed with flow cytometry on peripheral blood. Flow cytometric analysis confirmed depletion of CD8(+) cells (p amp;lt; 0.001). Contrary to our hypothesis, depletion of CD8(+) cells reduced the implant pull-out force by 19% (p amp;lt; 0.05) and stiffness by 34% (p amp;lt; 0.01), although the bone formation in the drill holes was the same as in the controls. Tendon healing was unaffected by CD8-depletion. Our results suggest that CD8(+) cells have an important part in cancellous bone healing.

  • 7.
    Björnsson Hallgren, Hanna Cecilia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla T
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Adolfsson, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Elevated plasma levels of TIMP-1 in patients with rotator cuff tear2012Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 83, nr 5, s. 523-528Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and purpose:Extracellular matrix remodelling is altered in rotator cuff tears,16partly due to altered expression of matrix metalloproteinases (MMPs) and their inhibitors. It is unclear if this altered expression can be traced as changes in plasma protein levels.

    The purposes were to measure the plasma level of MMPs and their tissue inhibitors (TIMPs) inpatients with rotator cuff tears and to relate changes in the pattern of MMP and TIMP levels with the extent of the rotator cuff tear.

    Methods: Blood samples were collected from 17 patients, median 61 (range 39-77) years, with sonographically verified rotator cuff tears (partial- or full-thickness). These were compared with 16 gender and age matched control persons with sonographically intact rotator cuffs. Plasma levels of MMPs and TIMPs were measured simultaneously using Luminex technology and ELISA.

    Results: The plasma level of TIMP-1 was elevated in patients with rotator cuff tears, especially in those with full-thickness tears. The levels of TIMP-1, TIMP-3 and MMP-9 were higher in patients with full-thickness tears compared to those with partial-thickness tears, but only TIMP-1 was different from controls.

    Interpretation: The observed elevation of TIMP-1 in plasma might reflect local pathological processes in or around the rotator cuff, or a genetic predisposition in these patients. That levels of TIMP-1 and certain MMP´s was found to differ between partial and full thickness tears may reflect the extent of the lesion or different aetiology and pathomechanisms.

  • 8.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Response to mechanical loading in healing tendons2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Ruptured tendons heal faster if they are exposed to mechanical loading. Loading creates deformation of the extracellular matrix and cells, which give rise to intracellular signalling, increased gene expression and protein synthesis. The effects of loading have been extensively studied in vitro, and in intact tendons in vivo. However, the response to loading in healing tendons is less known.

    The general aim of this thesis was to understand more about the response to mechanical loading during tendon healing. The specific aims were to find out how short daily loading episodes could influence tendon healing, and to understand more about genes involved in tendon healing.

    The studies were performed using rat models. Unloading of healing tendons resulted in a weaker callus tissue. This could be reversed to some extent by short daily loading episodes. Loading induced more matrix production, making the tendons thicker and stronger, but there was no improvement in the material properties of the matrix. Lengthening is one potential adversity with early loading, during tendon healing in patients. This was also seen with continuous loading in the rat models. However, short loading episodes did not result in any lengthening, not even when loading was applied during the inflammatory phase of healing. It also appeared as loading once daily was enough to make healing tendons stronger, while loading twice daily with 8 hours interval did not give any additional effect. The strongest gene expression response to one loading episode was seen after 3 hours. The gene expression changes persisted 12 hours after the loading episode but had disappeared by 24 hours. Loading appeared to regulate genes involved in inflammation, wound healing and coagulation, angiogenesis, and production of reactive oxygen species. Inflammation-associated genes were regulated both by continuous loading and by one short loading episode. Inflammation is an important part of the healing response, but too much can be harmful. Loading might therefore have a role in fine-tuning the inflammatory response during healing.

    In conclusion, these studies show that short daily loading episodes during early tendon healing could potentially be beneficial for rehabilitation. Loading might have a role in regulating the inflammatory response during healing.

    Delarbeid
    1. Tissue memory in healing tendons: short loading episodes stimulate healing
    Åpne denne publikasjonen i ny fane eller vindu >>Tissue memory in healing tendons: short loading episodes stimulate healing
    2009 (engelsk)Inngår i: JOURNAL OF APPLIED PHYSIOLOGY, ISSN 8750-7587, Vol. 107, nr 2, s. 417-421Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Intact tendons adapt slowly to changes in mechanical loading, whereas in healing tendons the effect of mechanical loading or its absence is dramatic. The longevity of the response to a single loading episode is, however, unknown. We hypothesized that the tissue has a "memory" of loading episodes and that therefore short loadings are sufficient to elicit improved healing. The Achilles tendon of 70 female rats was transected and unloaded by tail suspension for 12 days (suspension started on day 2 after surgery). Each day, the rats were let down from suspension for short daily training episodes according to different regimes: 15 min of cage activity or treadmill running for 15, 30, 60, or 2 x 15 min. Rats with transected Achilles tendons and full-time cage activity served as controls. The results demonstrated that full-time cage activity increased the peak force over three times compared with unloading. Short daily loading episodes (treadmill running) increased the peak force about half as much as full-time activity. Prolongation of treadmill running above 15 min or dividing the daily training in two separate episodes had minimal further effect. This mechanical stimulation increased the cross-sectional area but had no effect on the mechanical properties of the repair tissue. The findings indicate that once the tissue had received information from a certain loading type and level, this is "memorized" and leads to a response lasting many hours. This suggests that patients might be allowed early short loading episodes following, e. g., an Achilles tendon rupture for a better outcome.

    Emneord
    hindlimb suspension, immobilization, Achilles tendon, tendon healing, mechanical stimulation
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-19914 (URN)10.1152/japplphysiol.00414.2009 (DOI)
    Tilgjengelig fra: 2009-08-14 Laget: 2009-08-14 Sist oppdatert: 2012-03-27
    2. Achilles tendon healing in rats is improved by intermittent mechanical loading during the inflammatory phase
    Åpne denne publikasjonen i ny fane eller vindu >>Achilles tendon healing in rats is improved by intermittent mechanical loading during the inflammatory phase
    2012 (engelsk)Inngår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 30, nr 2, s. 274-279Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Tendons adapt to changes in mechanical loading, and numerous animal studiesshow that immobilization of a healing tendon is detrimental to the healingprocess. The present study addresses whether the effects of a few episodes ofmechanical loading are different during different phases of healing. Fifty femalerats underwent Achilles tendon transection, and their hind limbs were unloadedby tail suspension on the day after surgery. One group of 10 rats was taken downfrom suspension to walk on a treadmill for 30 minutes per day, on days 2-5 aftertransection. They were euthanized on day 8. Another group underwent similartreadmill running on days 8-11 and was euthanized on day 14. Completelyunloaded groups were euthanized on day 8 and 14. Tendon specimens were thenevaluated mechanically. The results showed that just 4 loading episodesincreased the strength of the healing tendon. This was evident irrespective of thetime-point when loading was applied (early or late). The positive effect on earlyhealing was unexpected, considering that the mechanical stimulation was appliedduring the inflammatory phase, when the calluses were small and fragile. Ahistological study of additional groups with early loading also showed someincreased bleeding in the loaded calluses. Our results indicate that a smallamount of early loading may improve the outcome of tendon healing. This couldbe of interest to clinical practice.

    sted, utgiver, år, opplag, sider
    Wiley Online Library, 2012
    Emneord
    Early loading, tail-suspension, unloading, mechanical testing, cell differentiation
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-70772 (URN)10.1002/jor.21511 (DOI)000298581200016 ()
    Merknad

    funding agencies|Swedish National Centre for Research in Sports||Swedish Research Council| VR 2009-6725 |Ostergotland County Council||

    Tilgjengelig fra: 2011-09-16 Laget: 2011-09-16 Sist oppdatert: 2017-12-08bibliografisk kontrollert
    3. Rat Achilles tendon healing: mechanical loading and gene expression
    Åpne denne publikasjonen i ny fane eller vindu >>Rat Achilles tendon healing: mechanical loading and gene expression
    2009 (engelsk)Inngår i: JOURNAL OF APPLIED PHYSIOLOGY, ISSN 8750-7587, Vol. 107, nr 2, s. 399-407Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Injured tendons require mechanical tension for optimal healing, but it is unclear which genes are upregulated and responsible for this effect. We unloaded one Achilles tendon in rats by Botox injections in the calf muscles. The tendon was then transected and left to heal. We studied mechanical properties of the tendon calluses, as well as mRNA expression, and compared them with loaded controls. Tendon calluses were studied 3, 8, 14, and 21 days after transection. Intact tendons were studied similarly for comparison. Altogether 110 rats were used. The genes were chosen for proteins marking inflammation, growth, extracellular matrix, and tendon specificity. In intact tendons, procollagen III and tenascin-C were more expressed in loaded than unloaded tendons, but none of the other genes was affected. In healing tendons, loading status had small effects on the selected genes. However, TNF-alpha transforming growth factor-beta 1, and procollagens I and III were less expressed in loaded callus tissue at day 3. At day 8 procollagens I and III, lysyl oxidase, and scleraxis had a lower expression in loaded calluses. However, by days 14 and 21, procollagen I, cartilage oligomeric matrix protein, tenascin-C, tenomodulin, and scleraxis were all more expressed in loaded calluses. In healing tendons, the transverse area was larger in loaded samples, but material properties were unaffected, or even impaired. Thus mechanical loading is important for growth of the callus but not its mechanical quality. The main effect of loading during healing might thereby be sought among growth stimulators. In the late phase of healing, tendon-specific genes (scleraxis and tenomodulin) were upregulated with loading, and the healing tissue might to some extent represent a regenerate rather than a scar.

    Emneord
    unloading, tendon healing, inflammation, extracellular matrix, mechanobiology
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-19899 (URN)10.1152/japplphysiol.91563.2008 (DOI)
    Tilgjengelig fra: 2009-08-14 Laget: 2009-08-14 Sist oppdatert: 2012-03-27
    4. Mechanical load and BMP signaling during tendon repair: A role for follistatin?
    Åpne denne publikasjonen i ny fane eller vindu >>Mechanical load and BMP signaling during tendon repair: A role for follistatin?
    2008 (engelsk)Inngår i: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 466, nr 7, s. 1592-1597Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Healing of the rat Achilles tendon is sensitive to mechanical loading, and the callus strength is reduced by 3/4 after 14 days, if loading is prevented. Exogenous GDFs stimulate tendon healing. This response is influenced by loading: without loading, cartilage and bone formation is initiated. This implies BMP signaling is crucial during tendon healing and influenced by mechanical loading. We therefore asked if mechanical loading influences the gene expression of the BMP signaling system in intact and healing tendons, and how the BMP signaling system changes during healing. The genes were four BMPs (OP-1/BMP-7, GDF-5/CDMP-1/BMP-14, GDF-6/CDMP2/BMP-13, and GDF-7/CDMP-3/BMP-12), two receptors (BMPR1b and BMPR2), and the antagonists follistatin and noggin. The Achilles tendon was transected in rats and left to heal. Half of the rats had one Achilles tendon unloaded by injection of Botox in the calf muscles. Ten tendons were analyzed before transection and for each of four time points. All genes except noggin were expressed at all points, but followed different patterns during healing. Loading strongly decreased the expression of follistatin, which could lead to increased signaling. The BMP system appears involved in tendon maintenance and healing, and may respond to mechanical loading.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-45883 (URN)10.1007/s11999-008-0253-0 (DOI)
    Tilgjengelig fra: 2009-10-11 Laget: 2009-10-11 Sist oppdatert: 2017-12-13
    5. Myostatin in tendon maintenance and repair
    Åpne denne publikasjonen i ny fane eller vindu >>Myostatin in tendon maintenance and repair
    Vise andre…
    2009 (engelsk)Inngår i: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 27, nr 4, s. 247-254Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Myostatin, a negative regulator of muscle growth, has recently been found to be expressed in tendons. Myostatin-deficient mice have weak and brittle tendons, which suggest that myostatin could be important for tendon maintenance. Follistatin expression in the callus tissue after tendon transection is influenced by loading. We found that follistatin antagonises myostatin, but not GDF-5 or OP-1 in vitro. To study if myostatin might play a physiological role in soft tissue, we transected 64 rat Achilles tendons and studied the gene expression for myostatin and its receptors at four different time-points during healing. Intact tendons were also studied. All samples were studied with or without mechanical loading. Unloading was achieved with botulinum toxin injections in the calf muscles. The expression of the myostatin gene was more than 40 times higher in intact tendons than in the callus tissue during tendon healing. The expression of myostatin was also influenced by loading status in both intact and healing tendons. Thereafter, we measured the mechanical properties of healing tendons after local myostatin administration. This treatment increased the volume and the contraction of the callus after 8 days, but did not improve its strength. Our results indicate that myostatin plays a positive role in tendon maintenance and that exogenous protein administration stimulates proliferation and growth of early repair tissue. However, no effect on further development towards connective tissue formation was found.

    Emneord
    GDF-8; myostatin; follistatin; gene expression; mechanical loading; Achilles tendon
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-20180 (URN)10.1080/08977190903052539 (DOI)
    Tilgjengelig fra: 2009-09-02 Laget: 2009-08-31 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    6. Influence of a single loading episode on gene expression in healing rat Achilles tendons
    Åpne denne publikasjonen i ny fane eller vindu >>Influence of a single loading episode on gene expression in healing rat Achilles tendons
    2012 (engelsk)Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 112, nr 2, s. 279-288Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Mechanical loading stimulates tendon healing via mechanisms that are largely unknown. Genes will be differently regulated in loaded healing tendons, compared to unloaded, just because of the fact that healing processes have been changed. In order to avoid such secondary effects and study the effect of loading per se, we therefore studied the gene expression response shortly after a single loading episode in otherwise unloaded healing tendons.

    The Achilles tendon was transected in 30 tail suspended rats. The animals were let down from the suspension to load their tendons on a treadmill for 30 min once, 5 days after tendon transection. Gene expression was studied by Affymetrix microarray before, and 3, 12, 24 and 48 h after loading. The strongest response in gene expression was seen 3 hours after loading, when 150 genes were up- or down-regulated (fold change≥ 2, p≤0.05). 12 hours after loading, only 3 genes were up-regulated, while 38 were down-regulated. Less than 7 genes were regulated after 24 and 48 hours. Genes involved in the inflammatory response were strongly regulated at 3 and 12 hours after loading; this included up-regulation of iNOS, PGE synthase, and IL-1β. Also genes involved in wound healing/coagulation, angiogenesis and production of reactive oxygen species were strongly regulated by loading. Microarray results were confirmed for 14 selected genes in a repeat experiment (N=30 rats) using real-time PCR. It was also confirmed that a single loading episode on day 5 increased the strength of the healing tendon on day 12. The fact that there were hardly any regulated genes 24 h after loading suggests that optimal stimulation of healing requires a mechanical loading stimulus every day.

    sted, utgiver, år, opplag, sider
    AMER PHYSIOLOGICAL SOC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA, 2012
    Emneord
    Gene expression, tendons, healing
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-70773 (URN)10.1152/japplphysiol.00858.2011 (DOI)000299318400006 ()
    Merknad
    funding agencies|Board of Research at the Karolinska Institute||Research Committee at the Karolinska Hospital||Swedish Research Council| 2009-6725 |Swedish National Centre for Research in Sports||King Gustaf V and Queen Victoria Free Mason Foundation||Tilgjengelig fra: 2011-09-16 Laget: 2011-09-16 Sist oppdatert: 2017-12-08bibliografisk kontrollert
  • 9.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Therese
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Influence of a single loading episode on gene expression in healing rat Achilles tendons2012Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 112, nr 2, s. 279-288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mechanical loading stimulates tendon healing via mechanisms that are largely unknown. Genes will be differently regulated in loaded healing tendons, compared to unloaded, just because of the fact that healing processes have been changed. In order to avoid such secondary effects and study the effect of loading per se, we therefore studied the gene expression response shortly after a single loading episode in otherwise unloaded healing tendons.

    The Achilles tendon was transected in 30 tail suspended rats. The animals were let down from the suspension to load their tendons on a treadmill for 30 min once, 5 days after tendon transection. Gene expression was studied by Affymetrix microarray before, and 3, 12, 24 and 48 h after loading. The strongest response in gene expression was seen 3 hours after loading, when 150 genes were up- or down-regulated (fold change≥ 2, p≤0.05). 12 hours after loading, only 3 genes were up-regulated, while 38 were down-regulated. Less than 7 genes were regulated after 24 and 48 hours. Genes involved in the inflammatory response were strongly regulated at 3 and 12 hours after loading; this included up-regulation of iNOS, PGE synthase, and IL-1β. Also genes involved in wound healing/coagulation, angiogenesis and production of reactive oxygen species were strongly regulated by loading. Microarray results were confirmed for 14 selected genes in a repeat experiment (N=30 rats) using real-time PCR. It was also confirmed that a single loading episode on day 5 increased the strength of the healing tendon on day 12. The fact that there were hardly any regulated genes 24 h after loading suggests that optimal stimulation of healing requires a mechanical loading stimulus every day.

  • 10.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Andersson, Therese
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Rat Achilles tendon healing: mechanical loading and gene expression2009Inngår i: JOURNAL OF APPLIED PHYSIOLOGY, ISSN 8750-7587, Vol. 107, nr 2, s. 399-407Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Injured tendons require mechanical tension for optimal healing, but it is unclear which genes are upregulated and responsible for this effect. We unloaded one Achilles tendon in rats by Botox injections in the calf muscles. The tendon was then transected and left to heal. We studied mechanical properties of the tendon calluses, as well as mRNA expression, and compared them with loaded controls. Tendon calluses were studied 3, 8, 14, and 21 days after transection. Intact tendons were studied similarly for comparison. Altogether 110 rats were used. The genes were chosen for proteins marking inflammation, growth, extracellular matrix, and tendon specificity. In intact tendons, procollagen III and tenascin-C were more expressed in loaded than unloaded tendons, but none of the other genes was affected. In healing tendons, loading status had small effects on the selected genes. However, TNF-alpha transforming growth factor-beta 1, and procollagens I and III were less expressed in loaded callus tissue at day 3. At day 8 procollagens I and III, lysyl oxidase, and scleraxis had a lower expression in loaded calluses. However, by days 14 and 21, procollagen I, cartilage oligomeric matrix protein, tenascin-C, tenomodulin, and scleraxis were all more expressed in loaded calluses. In healing tendons, the transverse area was larger in loaded samples, but material properties were unaffected, or even impaired. Thus mechanical loading is important for growth of the callus but not its mechanical quality. The main effect of loading during healing might thereby be sought among growth stimulators. In the late phase of healing, tendon-specific genes (scleraxis and tenomodulin) were upregulated with loading, and the healing tissue might to some extent represent a regenerate rather than a scar.

  • 11.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Andersson, Therese
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Hammerman, Malin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Primary gene response to mechanical loading in healing rat Achilles tendons2013Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 114, nr 11, s. 1519-1526Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Loading can stimulate tendon healing. In healing rat Achilles tendons, we have found more than 150 genes upregulated or downregulated 3 h after one loading episode. We hypothesized that these changes were preceded by a smaller number of regulatory genes and thus performed a microarray 15 min after a short loading episode, to capture the primary response to loading. We transected the Achilles tendon of 54 rats and allowed them to heal. The hind limbs were unloaded by tail-suspension during the entire experiment, except during the loading episode. The healing tendon tissue was analyzed by mechanical testing, microarray, and quantitative real-time polymerase chain reaction (qRT-PCR). Mechanical testing showed that 5 min of loading each day for 4 days created stronger tissue. The microarray analysis after one loading episode identified 15 regulated genes. Ten genes were analyzed in a repeat experiment with new rats using qRT-PCR. This confirmed the increased expression of four genes: early growth response 2 (Egr2), c-Fos, FosB, and regulation of G protein signaling 1 (Rgs1). The other genes were unaltered. We also analyzed the expression of early growth response 1 (Egr1), which is often coregulated with c-Fos or Egr2, and found that this was also increased after loading. Egr1, Egr2, c-Fos, and FosB are transcription factors that can be triggered by numerous stimuli. However, Egr1 and Egr2 are necessary for normal tendon development, and can induce ectopic expression of tendon markers. The five regulated genes appear to constitute a general activation machinery. The further development of gene regulation might depend on the tissue context.

  • 12.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Andersson, Therese
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Kulas, Jana
    Max Planck Institute.
    Seemann, Petra
    Max Planck Institute.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Myostatin in tendon maintenance and repair2009Inngår i: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 27, nr 4, s. 247-254Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Myostatin, a negative regulator of muscle growth, has recently been found to be expressed in tendons. Myostatin-deficient mice have weak and brittle tendons, which suggest that myostatin could be important for tendon maintenance. Follistatin expression in the callus tissue after tendon transection is influenced by loading. We found that follistatin antagonises myostatin, but not GDF-5 or OP-1 in vitro. To study if myostatin might play a physiological role in soft tissue, we transected 64 rat Achilles tendons and studied the gene expression for myostatin and its receptors at four different time-points during healing. Intact tendons were also studied. All samples were studied with or without mechanical loading. Unloading was achieved with botulinum toxin injections in the calf muscles. The expression of the myostatin gene was more than 40 times higher in intact tendons than in the callus tissue during tendon healing. The expression of myostatin was also influenced by loading status in both intact and healing tendons. Thereafter, we measured the mechanical properties of healing tendons after local myostatin administration. This treatment increased the volume and the contraction of the callus after 8 days, but did not improve its strength. Our results indicate that myostatin plays a positive role in tendon maintenance and that exogenous protein administration stimulates proliferation and growth of early repair tissue. However, no effect on further development towards connective tissue formation was found.

  • 13.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Mechanical load and BMP signaling during tendon repair: A role for follistatin?2008Inngår i: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 466, nr 7, s. 1592-1597Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Healing of the rat Achilles tendon is sensitive to mechanical loading, and the callus strength is reduced by 3/4 after 14 days, if loading is prevented. Exogenous GDFs stimulate tendon healing. This response is influenced by loading: without loading, cartilage and bone formation is initiated. This implies BMP signaling is crucial during tendon healing and influenced by mechanical loading. We therefore asked if mechanical loading influences the gene expression of the BMP signaling system in intact and healing tendons, and how the BMP signaling system changes during healing. The genes were four BMPs (OP-1/BMP-7, GDF-5/CDMP-1/BMP-14, GDF-6/CDMP2/BMP-13, and GDF-7/CDMP-3/BMP-12), two receptors (BMPR1b and BMPR2), and the antagonists follistatin and noggin. The Achilles tendon was transected in rats and left to heal. Half of the rats had one Achilles tendon unloaded by injection of Botox in the calf muscles. Ten tendons were analyzed before transection and for each of four time points. All genes except noggin were expressed at all points, but followed different patterns during healing. Loading strongly decreased the expression of follistatin, which could lead to increased signaling. The BMP system appears involved in tendon maintenance and healing, and may respond to mechanical loading.

  • 14.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Pasternak, Björn
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Unloaded rat Achilles tendons continue to grow, but lose viscoelasticity2007Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 103, nr 2, s. 459-463Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tendons can function as springs and thereby preserve energy during cyclic loading. They might also have damping properties, which, hypothetically, could reduce risk of microinjuries due to fatigue at sites of local stress concentration within the tendon. At mechanical testing, damping will appear as hysteresis. How is damping influenced by training or disuse? Does training decrease hysteresis, thereby making the tendon a better spring, or increase hysteresis and thus improve damping? Seventy-eight female 10-wk-old Sprague-Dawley rats were randomized to three groups. Two groups had botulinum toxin injected into the calf muscles to unload the left Achilles tendon through muscle paralysis. One of these groups was given doxycycline, as a systemic matrix metalloproteinase inhibitor. The third group served as loaded controls. The Achilles tendons were harvested after 1 or 6 wk for biomechanical testing. An increase with time was seen in tendon dry weight, wet weight, water content, transverse area, length, stiffness, force at failure, and energy uptake in all three groups (P < 0.001 for each parameter). Disuse had no effect on these parameters. Creep was decreased with time in all groups. The only significant effect of disuse was on hysteresis (P = 0.004) and creep (P = 0.007), which both decreased with disuse compared with control, and on modulus, which was increased (P = 0.008). Normalized glycosaminoglycan content was unaffected by time and disuse. No effect of doxycycline was observed. The results suggest that in growing animals, the tendons continue to grow regardless of mechanical loading history, whereas maintenance of damping properties requires mechanical stimulation.

  • 15.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Svensson, Rene B.
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Giannopoulos, Antonis
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Eismark, Christian
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Kjaer, Michael
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Schjerling, Peter
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Heinemeier, Katja M.
    Bispebjerg Hospital, Denmark; University of Copenhagen, Denmark.
    Simvastatin and atorvastatin reduce the mechanical properties of tendon constructs in vitro and introduce catabolic changes in the gene expression pattern2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 3, artikkel-id e0172797Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Treatment with lipid-lowering drugs, statins, is common all over the world. Lately, the occurrence of spontaneous tendon ruptures or tendinosis have suggested a negative influence of statins upon tendon tissue. But how statins might influence tendons is not clear. In the present study, we investigated the effect of statin treatment on mechanical strength, cell proliferation, collagen content and gene expression pattern in a tendon-like tissue made from human tenocytes in vitro. Human tendon fibroblasts were grown in a 3D tissue culture model (tendon constructs), and treated with either simvastatin or atorvastatin, low or high dose, respectively, for up to seven days. After seven days of treatment, mechanical testing of the constructs was performed. Collagen content and cell proliferation were also determined. mRNA levels of several target genes were measured after one or seven days. The maximum force and stiffness were reduced by both statins after 7 days (pamp;lt;0.05), while the cross sectional area was unaffected. Further, the collagen content was reduced by atorvastatin (p = 0.01) and the cell proliferation rate was decreased by both types of statins (pamp;lt;0.05). Statin treatment also introduced increased mRNA levels of MMP-1, MMP-3, MMP-13, TIMP-1 and decreased levels of collagen type 1 and 3. In conclusion, statin treatment appears to have a negative effect on tendon matrix quality as seen by a reduced strength of the tendon constructs. Further, activated catabolic changes in the gene expression pattern and a reduced collagen content indicated a disturbed balance in matrix production of tendon due to statin administration.

  • 16.
    Hammerman, Malin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Microtrauma stimulates rat Achilles tendon healing via an early gene expression pattern similar to mechanical loading2014Inngår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 116, nr 1, s. 54-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mechanical loading increases the strength of healing tendons, but also induces small localized bleedings. Therefore, it is unclear if increased strength after loading is a response to mechanotransduction or microtrauma. We have previously found only five genes to be up-regulated 15 min after a single loading episode, of them four were transcription factors. These genes are followed by hundreds of genes after 3 h, many of them involved in inflammation. We now compared healing in mechanically unloaded tendons with or without added microtrauma induced by needling of the healing tissue. Nineteen rats received Botox into the calf muscle to reduce loading, and the Achilles tendon was transected. Ten rats were randomized to needling days 2-5. Mechanical testing on day 8 showed increased strength by 45% in the needling group. Next, another 24 rats were similarly unloaded, and 16 randomized to needling on day 5 after transection. Nineteen characteristic genes, known to be regulated by loading in this model, were analyzed by qRT-PCR. Four of these genes were regulated 15 min after needling. Three of them (Egr1, c-Fos, Rgs1) were among the five regulated genes after loading in a previous study. Sixteen of the 19 genes were regulated after 3 h, in the same way as after loading. In conclusion, needling increased strength, and there was a striking similarity between the gene expression response to needling and mechanical loading. This suggests that the response to loading in early tendon healing can, at least in part, be a response to microtrauma.

  • 17.
    Khayyeri, Hanifeh
    et al.
    Lund University, Sweden.
    Gustafsson, Anna
    Lund University, Sweden.
    Heuijerjans, Ashley
    Eindhoven University of Technology, Netherlands.
    Matikainen, Marko K.
    Lappeenranta University of Technology, Finland.
    Julkunen, Petro
    Kuopio University Hospital, Finland; University of Eastern Finland, Finland.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Isaksson, Hanna
    Lund University, Sweden.
    A Fibre-Reinforced Poroviscoelastic Model Accurately Describes the Biomechanical Behaviour of the Rat Achilles Tendon2015Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 6, artikkel-id e0126869Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Computational models of Achilles tendons can help understanding how healthy tendons are affected by repetitive loading and how the different tissue constituents contribute to the tendons biomechanical response. However, available models of Achilles tendon are limited in their description of the hierarchical multi-structural composition of the tissue. This study hypothesised that a poroviscoelastic fibre-reinforced model, previously successful in capturing cartilage biomechanical behaviour, can depict the biomechanical behaviour of the rat Achilles tendon found experimentally. Materials and Methods We developed a new material model of the Achilles tendon, which considers the tendons main constituents namely: water, proteoglycan matrix and collagen fibres. A hyperelastic formulation of the proteoglycan matrix enabled computations of large deformations of the tendon, and collagen fibres were modelled as viscoelastic. Specimen-specific finite element models were created of 9 rat Achilles tendons from an animal experiment and simulations were carried out following a repetitive tensile loading protocol. The material model parameters were calibrated against data from the rats by minimising the root mean squared error (RMS) between experimental force data and model output. Results and Conclusions All specimen models were successfully fitted to experimental data with high accuracy (RMS 0.42-1.02). Additional simulations predicted more compliant and soft tendon behaviour at reduced strain-rates compared to higher strain-rates that produce a stiff and brittle tendon response. Stress-relaxation simulations exhibited strain-dependent stress-relaxation behaviour where larger strains produced slower relaxation rates compared to smaller strain levels. Our simulations showed that the collagen fibres in the Achilles tendon are the main load-bearing component during tensile loading, where the orientation of the collagen fibres plays an important role for the tendons viscoelastic response. In conclusion, this model can capture the repetitive loading and unloading behaviour of intact and healthy Achilles tendons, which is a critical first step towards understanding tendon homeostasis and function as this biomechanical response changes in diseased tendons.

  • 18.
    Lundin, Anna-Carin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Eliasson, Pernilla T.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Trigger finger, tendinosis, and intratendinous gene expression2014Inngår i: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 24, nr 2, s. 363-368Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pathogenesis of trigger finger has generally been ascribed to primary changes in the first annular ligament. In contrast, we recently found histological changes in the tendons, similar to the findings in Achilles tendinosis or tendinopathy. We therefore hypothesized that trigger finger tendons would show differences in gene expression in comparison to normal tendons in a pattern similar to what is published for Achilles tendinosis. We performed quantitative real-time polymerase chain reaction on biopsies from finger flexor tendons, 13 trigger fingers and 13 apparently healthy control tendons, to assess the expression of 10 genes which have been described to be differently expressed in tendinosis (collagen type 1a1, collagen 3a1, MMP-2, MMP-3, ADAMTS-5, TIMP-3, aggrecan, biglycan, decorin, and versican). In trigger finger tendons, collagen types 1a1 and 3a1, aggrecan and biglycan were all up-regulated, and MMP-3and TIMP-3 were down-regulated. These changes were statistically significant and have been previously described for Achilles tendinosis. The remaining four genes were not significantly altered. The changes in gene expression support the hypothesis that trigger finger is a form of tendinosis. Because trigger finger is a common condition, often treated surgically, it could provide opportunities for clinical research on tendinosis.

  • 19.
    Lundin, Anna-Carin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Hand och plastikkirurgi. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Trigger finger and tendinosis2012Inngår i: Journal of Hand Surgery, European Volume, ISSN 1753-1934, E-ISSN 2043-6289, Vol. 37, nr 3, s. 233-236Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The pathogenesis of trigger finger has generally been ascribed to primary changes in the pulley. Histological examination of the affected tendons has rarely been done. We studied biopsies from tendons of trigger fingers from 29 patients and compared these to biopsies from six intact tendons. We used a modified Movin score, which describes the tendinosis of the Achilles tendon. Trigger finger tendons had a high score (14.2; SD, 2.2) consistent with tendinosis, while the controls were almost normal (2.5; SD, 1.9). This suggests that the tendon is also affected, and that trigger finger is a form of tendinosis.

  • 20.
    Pasternak, Björn
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Schepull, Thorsten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Elevation of systemic matrix metalloproteinase-2 and -7 and tissue inhibitor of metalloproteinases-2 in patients with a history of Achilles tendon rupture2010Inngår i: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 38, s. 308-317Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: To compare serum levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) between patients with a history of Achilles tendon rupture and blood donor controls, and to relate MMPs and TIMPs to mechanical properties of the tendons during healing.

    Methods: More than three years after injury, we measured serum levels of MMP-1, -2, -3, -7, -8, -9 and -13 and TIMP-1 and -2 in eight patients who had suffered Achilles tendon rupture. Twelve blood donors served as controls. During the early phase of healing, the tendon modulus of elasticity was calculated from radiostereometric data and tendon cross-sectional area.

    Results: Patients with a history of Achilles tendon rupture had increased levels of MMP-2 (median difference (m.d.) 10 %; p = 0.01), MMP-7 (m.d. 15 %; p = 0.02) and TIMP-2 (m.d. 36%; p = 0.02), as compared to controls. Levels of MMP-7, measured three years after injury, correlated inversely to tendon modulus of elasticity (rs = -0.83; p = 0.02), and positively to tendon elongation (rs = 0.74; p = 0.05) during the early phase of healing. There was a trend towards positive correlation between MMP-7 and cross-sectional area during the early phase of healing (rs = 0.67; p = 0.08).

    Conclusions: Patients with a history of Achilles tendon rupture appear to have elevated levels of MMP-2, MMP-7 and TIMP-2 in serum. These pilot data support the view that the MMP-TIMP system is involved in tendinopathy and suggest that disturbances in proteolytic control might be generalised.

  • 21.
    Sandberg, Olof
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Dånmark, Ida
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Eliasson, Pernilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Influence of a lower leg brace on traction force in healthy and ruptured Achilles tendons2015Inngår i: MLTJ Muscles, Ligaments and Tendons Journal, ISSN 2240-4554, Vol. 5, nr 2, s. 63-67Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background: we investigated how ruptured Achilles tendons are loaded in a brace. There is an ongoing discussion whether patients should be recommended to bear weight on the injuredlimb. However, little is known about the effects of bracing on tensional loading of the healing Achilles tendon: it is uncertain if load-bearing actually stresses the Achilles tendon inside a brace.

    Methods: we measured plantar flexion moment inside the brace, in order to estimate tensional loading of the tendon, by use of an insole with pressure transducers.

    Results: after wearing the brace for 1 hour, young healthy individuals reduced their maximum flexion moment during gait by half. Patients with Achilles tendon rupture showed no measurable flexion moment during gait with the brace, 4 or 7 weeks after injury. Only when specifically instructed, they could produce a considerable plantar flexion moment. We noted that gait speed with the brace at 4 weeks correlated with a heel-raise functional test at 1 year: the higher the spontaneous gait speed, the less the functional difference between the injured and the uninjured leg (r2=0.68; p=0.002).

    Conclusion: the correlation with gait speed suggests that the patients’ general physical aptness has an impact on the end result.

  • 22.
    Sandberg, Olof
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Eliasson, Pernilla T
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin.
    Andersson, Therese
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Etanercept does not impair healing in rat models of tendon or metaphyseal bone injury2012Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 83, nr 3, s. 305-310Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and purpose Should blockade of TNF-alpha be avoided after orthopedic surgery? Healing of injuries in soft tissues and bone starts with a brief inflammatory phase. Modulation of inflammatory signaling might therefore interfere with healing. For example, Cox inhibitors impair healing in animal models of tendon, ligament, and bone injury, as well as in fracture patients. TNF-alpha is expressed locally at increased levels during early healing of these tissues. We therefore investigated whether blocking of TNF-alpha with etanercept influences the healing process in established rat models of injury of tendons and metaphyseal bone. less thanbrgreater than less thanbrgreater thanMethods Rats were injected with etanercept, 3.5 mg/kg 3 times a week. Healing of transected Achilles tendons and bone healing around screws implanted in the tibial metaphysis were estimated by mechanical testing. Tendons were allowed to heal either with or without mechanical loading. Ectopic bone induction following intramuscular BMP-2 implants has previously been shown to be stimulated by etanercept in rodents. This was now tested as a positive control. less thanbrgreater than less thanbrgreater thanResults Tendon peak force after 10 days was not significantly influenced by etanercept. Changes exceeding 29% could be excluded with 95% confidence. Likewise, screw pull-out force was not significantly influenced. More than 25% decrease or 18% increase could be excluded with 95% confidence. However, etanercept treatment increased the amount of bone induced by intramuscular BMP-2 implants, as estimated by blind histological scoring. less thanbrgreater than less thanbrgreater thanInterpretation Etanercept does not appear to impair tendon or metaphyseal bone healing to any substantial degree.

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