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  • 1.
    Abtahi, Jahan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Käkkliniken US.
    Agholme, Fredrik
    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.
    Prevention of osteonecrosis of the jaw by mucoperiosteal coverage in a rat model2013Ingår i: International Journal of Oral and Maxillofacial Surgery, ISSN 0901-5027, E-ISSN 1399-0020, Vol. 42, nr 5, s. 632-636Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There is evidence for a link between the use of systemic bisphosphonates and osteonecrosis of the jaw (ONJ). This condition has the appearance of chronic osteomyelitis, and antibiotics prevent the development of ONJ in animal models. Clinically, ONJ can sometimes be successfully treated by mucoperiosteal coverage. If ONJ is indeed primarily caused by bacterial infection, immediate coverage of the extraction alveolus might reduce the risk of ONJ development in risk patients. Therefore, we studied whether immediate mucoperiosteal coverage after tooth extraction could prevent ONJ development in a rat model. Thirty rats were randomly allocated to three groups of 10. Group I (controls): extraction, no drug treatment; Group II (non-coverage): extraction, dexamethasone plus alendronate; Group III (coverage): dexamethasone plus alendronate, plus coverage by a mucoperiosteal flap. Rats were examined for macroscopic ONJ-like wounds after 2 weeks. All animals in the non-coverage group developed large ONJ-like changes. The coverage and control groups showed an intact overlying mucosa in all rats. Findings were confirmed with histology. Bisphosphonates and dexamethasone caused ONJ-like lesions after tooth extraction in a rat model. This was prevented by immediate mucoperiosteal coverage. The risk of ONJ in patients using bisphosphonates might be reduced by mucoperiosteal coverage after tooth extraction.

  • 2.
    Abtahi, Jahan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Käkkliniken US.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Sandberg, Olof
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Bisphosphonate-induced osteonecrosis of the jaw in a rat model arises first after the bone has become exposed. No primary necrosis in unexposed bone2012Ingår i: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 41, nr 6, s. 494-499Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    J Oral Pathol Med (2012) 41: 494499 Background: Bisphosphonate-related osteonecrosis of the jaw was first described to start with sterile osteocyte death, similar to osteonecrosis in other parts of the skeleton. The typical chronic osteomyelitis was thought to develop when the dead bone was exposed to the oral cavity. An alternative explanation would be that the chronic osteomyelitis is a result of a bisphosphonate-related inability of infected bony lesions to heal. We tested the hypothesis that primary osteocyte death is not necessary for the development of jaw osteonecrosis. Material and methods: Forty rats were randomly allocated to four groups of 10. All animals underwent unilateral molar extraction and received the following drug treatments: Group I, controls with no drug treatment; Group II, 200 mu g/kg per day alendronate; Groups III and IV, 200 mu g/kg per day alendronate and 1 mg/kg of dexamethasone. All rats were euthanized after 14 days. Presence of osteonecrosis was determined by clinical and histological observations for groups IIII. For group IV, osteocyte viability at the contralateral uninjured site was examined using lactate dehydrogenase histochemistry (LDH). Results: All animals in the alendronate plus dexamethasone groups developed large ONJ-like lesions. Lactate dehydrogenase staining showed viable osteocytes in the contralateral jaw with no tooth extraction. No signs of osteonecosis were seen in the other groups. Conclusion: Bisphosphonates and dexamethasone caused no osteocyte death in uninjured bone, but large ONJ-like lesions after tooth extraction. Osteonecrosis of the jaw appears to arise first after the bone has been exposed. Possibly, bisphosphonates hamper the necessary resorption of bone that has become altered because of infection.

  • 3.
    Abtahi, Jahan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Käkkliniken US.
    Agholme, Fredrik
    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.
    Effect of Local vs. Systemic Bisphosphonate Delivery on Dental Implant Fixation in a Model of Osteonecrosis of the Jaw2013Ingår i: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 92, nr 3, s. 279-283Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Locally applied bisphosphonates may improve the fixation of metal implants in bone. However, systemic bisphosphonate treatment is associated with a risk of osteonecrosis of the jaw (ONJ). We hypothesized that local delivery of bisphosphonate from the implant surface improves the fixation of dental implants without complications in a setting where systemic treatment induces ONJ. Forty rats were randomly allocated to 4 groups of 10. All groups received a titanium implant inserted in an extraction socket. Group I received the implants only. Group II received dexamethasone (0.5 mg/kg). Group III received dexamethasone as above plus alendronate (200 µg/kg). Group IV received zoledronate-coated implants and dexamethasone as above. The animals were sacrificed 2 weeks after tooth extraction. All 10 animals with systemic alendronate treatment developed large ONJ-like changes, while all with local treatment were completely healed. Implant removal torque was higher for the bisphosphonate-coated implants compared with the other groups (p < 0.03 for each comparison). Micro-computed tomography of the maxilla showed more bone loss in the systemic alendronate group compared with groups receiving local treatment (p = 0.001). Local bisphosphonate treatment appears to improve implant fixation in a setting where systemic treatment caused ONJ.

  • 4.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Wnt signaling and metaphyseal bone healing2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis relates to some new aspects on the regulation of bone healing. In the last few years, Wnt-signaling has been shown to play a central role in bone biology. As well as being involved in bone maintenance and repair, Wnt-signaling has been presented as one of the key pathways through which bone responds to mechanical load. Two secreted extracellular inhibitors of Wnt-signaling, sclerostin and dickkopf-1 are potent negative regulators of bone formation.

    Using a rat fracture model we investigated how metaphyseal bone healing is influenced by changes in Wnt-signaling.

    Antibodies were used to suppress levels of sclerostin and dickkopf-1, and thereby increase Wnt-signaling. Primarily, we investigated if those antibody treatments lead to improved bone healing. Also, we investigated if the response was coupled to the loading conditions of the bone.

    Our findings suggest that suppression of either sclerostin or dickkopf-1 leads to increased bone formation and improved bone healing. Apart from just having an effect on healing, the treatment also improved bone formation in other parts of the skeleton. Depending on the loading conditions, the effects were different. Dickkopf-1 appeared to have a stronger effect on bone volume density in unloaded bone, implying a role mainly in mechano-transduction, while sclerostin had similar effect in both loaded and unloaded bone. To confirm these findings, we studied how the expression of several Wnt-related genes changed due to trauma and unloading in metaphyseal bone. We found that trauma led to upregulation of most of the genes with the largest effect seen in the unloaded bone. In untraumatized bone, there was mainly an effect on the sclerostin gene.

    In conclusion, antibodies against sclerostin and dickkopf-1 appear to be able to improve metaphyseal bone healing. There appear to be some differences in how the effect of the two antibodies manifests itself, especially if the loading conditions of the bone are altered. These findings suggest a potential for clinical use to shorten fracture healing time.

    Delarbeten
    1. Sclerostin Antibody Treatment Enhances Metaphyseal Bone Healing in Rats
    Öppna denna publikation i ny flik eller fönster >>Sclerostin Antibody Treatment Enhances Metaphyseal Bone Healing in Rats
    Visa övriga...
    2010 (Engelska)Ingår i: JOURNAL OF BONE AND MINERAL RESEARCH, ISSN 0884-0431, Vol. 25, nr 11, s. 2412-2418Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Sclerostin is the product of the SOST gene Loss of-function mutations in the SOST gene result in a high bone-mass phenotype demonstrating that sclerostin is a negative regulator of bone mass Primarily expressed by osteocytes in bone sclerostin is reported to bind the LRP5/6 receptor thereby antagonizing canonical Wnt signaling and negatively regulating bone formation We therefore investigated whether systemic administration of a sclerostin neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks In four groups, the screws were tested for pull out strength At the time of euthanasia a similar screw also was inserted in the contralateral tibia and pull-out tested immediately Sclerostin antibody significantly increased the pull out force by almost 50% compared with controls after 2 and 4 weeks Also the screws inserted at the time of euthanasia showed increased pull out force Micro-computed tomography (mu CT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw There also was a general increase in trabecular thickness in cancellous bone Thus as measured by the amount of bone and its mechanical resistance the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone

    Ort, förlag, år, upplaga, sidor
    American Society for Bone and Mineral Research, 2010
    Nyckelord
    bone formation;implants;bone repair;sclerostin;antibody
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-62733 (URN)10.1002/jbmr.135 (DOI)000284133500016 ()20499342 (PubMedID)
    Tillgänglig från: 2010-12-03 Skapad: 2010-12-03 Senast uppdaterad: 2011-10-10
    2. The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions
    Öppna denna publikation i ny flik eller fönster >>The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions
    2011 (Engelska)Ingår i: BONE, ISSN 8756-3282, Vol. 48, nr 5, s. 988-996Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, mu CT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botulinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233%. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

    Ort, förlag, år, upplaga, sidor
    Elsevier Science B.V., Amsterdam., 2011
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-68352 (URN)10.1016/j.bone.2011.02.008 (DOI)000289879900005 ()
    Anmärkning
    Original Publication: Fredrik Agholme, Hanna Isaksson, Stuart Kuhstoss and Per Aspenberg, The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions, 2011, BONE, (48), 5, 988-996. http://dx.doi.org/10.1016/j.bone.2011.02.008 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/ Tillgänglig från: 2011-05-20 Skapad: 2011-05-20 Senast uppdaterad: 2011-10-10
    3. Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats
    Öppna denna publikation i ny flik eller fönster >>Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats
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    2011 (Engelska)Ingår i: Acta Orthopaedica, ISSN 1745-3674, Vol. 82, nr 5, s. 628-632Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background and purpose: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model.

    Methods: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma.

    Results: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force.

    Interpretation: Scl-Ab increases bone formation and screwfixation to a similar degree in loaded and unloaded bone.

    Ort, förlag, år, upplaga, sidor
    Taylor and Francis, 2011
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-71284 (URN)10.3109/17453674.2011.625539 (DOI)
    Tillgänglig från: 2011-10-10 Skapad: 2011-10-10 Senast uppdaterad: 2014-10-17Bibliografiskt granskad
    4. Wnt gene expression during metaphyseal bone healing under different load conditions
    Öppna denna publikation i ny flik eller fönster >>Wnt gene expression during metaphyseal bone healing under different load conditions
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Bone Wnt signalling has been presented as one of the key pathways through which bone responds to mechanical load. This pathway is also active during the healing process after bone trauma. Bone healing can be improved by pharmacological modulation of Wnt signalling. We investigated how the expression of several Wntrelated genes changed due to trauma and unloading in metaphyseal bone.

    20 male rats had one hind limb unloaded by intramuscular Botox injections. In half of the animals a hole was drilled bilaterally in the proximal tibia. After 7 days, a cylindrical biopsy was taken from the bone surrounding the hole and at a corresponding site in animals without trauma. The biopsies were analyzed for the mRNA expression of Wnt1, Wnt3a, Wnt4, Wnt5a, Wnt5b, Sost, Dkk1, Dkk2, Sfrp1, Sfrp4, Lrp5, Lrp6, Wisp1, Wif1 and Wnt10b.

    Trauma led to upregulation of most of the studied genes. This effect was most evident in unloaded bone, where 8 genes were upregulated, among them Wnt receptors, ligands and inhibitors. Unloading increased the expression of Sost in untraumatized bone, but did not significantly influence the other genes.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-71285 (URN)
    Tillgänglig från: 2011-10-10 Skapad: 2011-10-10 Senast uppdaterad: 2011-10-10Bibliografiskt granskad
  • 5.
    Agholme, Fredrik
    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. Linköpings universitet, Hälsouniversitetet.
    Tengvall, P
    University of Gothenburg.
    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.
    Local bisphosphonate release versus hydroxyapatite coating for stainless steel screw fixation in rat tibiae2012Ingår i: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 23, nr 3, s. 743-752Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Implant fixation in bone can be improved by a coating that delivers bisphosphonates locally, or by a hydroxyapatite (HA) coating. In this study, we compared these different types of coatings. For mechanical testing, 30 rats were assigned into three groups, and similar screws were implanted bilaterally in the proximal tibiae. The rats received screws that were either uncoated, coated with nano-crystalline hydroxyapatite or coated with a bisphosphonate releasing protein matrix. After 4 weeks, one screw was subjected to pull-out testing, and the contra-lateral one to torsion testing. For morphology, 30 rats were assigned to similar treatment groups, but received only one screw each. Bisphosphonates enhanced the pull-out force by 41% (P = 0.02) compared to controls, HA increased the pull-out force although not significantly. Conversely, HA increased the maximal torque by 64% (P = 0.02). Morphometry showed higher bone volume around bisphosphonate screws in comparison to HA-coated screws (P andlt; 0.001) and controls (P andlt; 0.001). The results suggest that bisphosphonates improve fixation by increasing the amount of surrounding bone, whereas HA mainly improves bone to implant attachment.

  • 6.
    Agholme, Fredrik
    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. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    University of Gothenburg.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    A win for bisphosphonates? Comparison between local bisphosphonate release and hydroxyapatite coating for screw fixation in rats in BONE, vol 46, issue , pp S67-S672010Ingår i: BONE, Elsevier Science B.V., Amsterdam. , 2010, Vol. 46, s. S67-S67Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 7.
    Agholme, Fredrik
    et al.
    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.
    Experimental results of combining bisphosphonates with allograft in a rat model2009Ingår i: Journal of Bone and Joint Surgery - Series B, ISSN 0301-620X, Vol. 91, nr 5, s. 670-675Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Soaking bone grafts in a bisphosphonate solution before implantation can prevent their resorption and increase the local bone density in rats and humans. However, recent studies suggest that pre-treatment of allografts with bisphosphonate can prevent bone ingrowth into impaction grafts. We tested the hypothesis that excessive amounts of bisphosphonate would also cause a negative response in less dense grafts. We used a model where nonimpacted metaphyseal bone grafts were randomised into three groups with either no bisphosphonate, alendronate followed by rinsing, and alendronate without subsequent rinsing, and inserted into bone chambers in rats. The specimens were evaluated histologically at one week, and by histomorphometry and radiology at four weeks. At four weeks, both bisphosphonate groups showed an increase in the total bone content, increased newly formed bone, and higher radiodensity than the controls. In spite of being implanted in a chamber with a limited opportunity to diffuse, even an excessive amount of bisphosphonate improved the outcome. We suggest that the negative results seen by others could be due to the combination of densely compacted bone and a bisphosphonate. We suggest that bisphosphonates are likely to have a negative influence where resorption is a prerequisite to create space for new bone ingrowth.

  • 8.
    Agholme, Fredrik
    et al.
    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.
    Reduced serum serotonin impairs metaphyseal repair in rats in BONE, vol 46, issue , pp S67-S672010Ingår i: BONE, Elsevier Science B.V., Amsterdam. , 2010, Vol. 46, s. S67-S67Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 9.
    Agholme, Fredrik
    et al.
    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.
    Wnt signaling and orthopedics, an overview2011Ingår i: ACTA ORTHOPAEDICA, ISSN 1745-3674, Vol. 82, nr 2, s. 125-130Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wnt signaling is a ubiquitous system for intercellular communication, with multiple functions during development and in homeostasis of the body. It comprises several ligands, receptors, and inhibitors. Some molecules, such as sclerostin, appear to have bone-specific functions, and can be targeted by potential drugs. Now, ongoing clinical trials are testing these drugs as treatments for osteoporosis. Animal studies have also suggested that these drugs can accelerate fracture healing and implant fixation. This brief overview focuses on currently available information on the effects of manipulations of Wnt signaling on bone healing.

  • 10.
    Agholme, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Isaksson, Hanna
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Kuhstoss, Stuart
    Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, USA.
    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.
    The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions2011Ingår i: BONE, ISSN 8756-3282, Vol. 48, nr 5, s. 988-996Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, mu CT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botulinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233%. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

  • 11.
    Agholme, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Isaksson, Hanna
    Department of Applied physics, University of Eastern Finland, Kuopio, Finland.
    Li, Xiaodong
    Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
    Ke, Hua Zhu
    Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
    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.
    Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats2011Ingår i: Acta Orthopaedica, ISSN 1745-3674, Vol. 82, nr 5, s. 628-632Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and purpose: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model.

    Methods: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma.

    Results: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force.

    Interpretation: Scl-Ab increases bone formation and screwfixation to a similar degree in loaded and unloaded bone.

  • 12.
    Agholme, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Li, Xiaodong
    Amgen Inc.
    Isaksson, Hanna
    University of Eastern Finland.
    Zhu Ke, Hua
    Amgen Inc.
    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.
    Sclerostin Antibody Treatment Enhances Metaphyseal Bone Healing in Rats2010Ingår i: JOURNAL OF BONE AND MINERAL RESEARCH, ISSN 0884-0431, Vol. 25, nr 11, s. 2412-2418Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sclerostin is the product of the SOST gene Loss of-function mutations in the SOST gene result in a high bone-mass phenotype demonstrating that sclerostin is a negative regulator of bone mass Primarily expressed by osteocytes in bone sclerostin is reported to bind the LRP5/6 receptor thereby antagonizing canonical Wnt signaling and negatively regulating bone formation We therefore investigated whether systemic administration of a sclerostin neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks In four groups, the screws were tested for pull out strength At the time of euthanasia a similar screw also was inserted in the contralateral tibia and pull-out tested immediately Sclerostin antibody significantly increased the pull out force by almost 50% compared with controls after 2 and 4 weeks Also the screws inserted at the time of euthanasia showed increased pull out force Micro-computed tomography (mu CT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw There also was a general increase in trabecular thickness in cancellous bone Thus as measured by the amount of bone and its mechanical resistance the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone

  • 13.
    Agholme, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Macias, Brandon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Hamang, Matt
    Lilly Research Labs, IN USA .
    Lucchesi, Jonathan
    Lilly Research Labs, IN USA .
    Adrian, Mary D.
    Lilly Research Labs, IN USA .
    Kuhstoss, Stuart
    Lilly Research Labs, IN USA .
    Harvey, Anita
    Lilly Research Labs, IN USA .
    Sato, Masahiko
    Lilly Research Labs, IN USA .
    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.
    Efficacy of a Sclerostin Antibody Compared to a Low Dose of PTH on Metaphyseal Bone Healing2014Ingår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 32, nr 3, s. 471-476Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We compared the effect of a sclerostin antibody to that of a clinically relevant dose of parathyroid hormone (PTH) in a rat model for metaphyseal bone healing. Screws of steel or poly methyl methacrylate (PMMA) were inserted bilaterally into the proximal tibia of young male rats. During 4 weeks the animals then received injections of either phosphate buffered saline (control), sclerostin antibody (25mg/kg, twice weekly) or PTH (5 mu g/kg, daily). The healing response around the screws was then assessed by mechanical testing and X-ray microtomography (mu CT). To distinguish between effects on healing and general effects on the skeleton, other untraumatized bone sites and serum biomarkers were also assessed. After 4 weeks of treatment, PTH yielded a 48% increase in screw pull-out force compared to control (p=0.03), while the antibody had no significant effect. In contrast, the antibody increased femoral cortical and vertebral strength where PTH had no significant effect. mu CT showed only slight changes that were statistically significant for the antibody mainly at cortical sites. The results suggest that a relatively low dose of PTH stimulates metaphyseal repair (screw fixation) specifically, whereas the sclerostin antibody has wide-spread effects, mainly on cortical bone, with less influence on metaphyseal healing.

  • 14.
    Andersson, Therese
    et al.
    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, Ortopedicentrum, Ortopedkliniken Linköping.
    Tengvall, Pentti
    Gothenburg University.
    Surface immobilized zoledronate improves screw fixation in rat bone: A new method for the coating of metal implants2010Ingår i: JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE, ISSN 0957-4530, Vol. 21, nr 11, s. 3029-3037Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous studies show that surface immobilized bisphosphonates improve the fixation of stainless steel screws in rat tibia after 2-8 weeks of implantation. We report here about the immobilization of a potent bisphosphonate, zoledronate, to crosslinked fibrinogen by the use of another technique, i.e. ethyl-dimethyl-aminopropylcarbodiimide (EDC)/imidazole immobilization. Bone fixation of zoledronate-coated screws was compared to screws coated with crosslinked fibrinogen only and ditto with EDC/N-hydroxy-succinimide immobilized pamidronate. Fixation in rat tibia was evaluated by a pull-out test at either 2 or 6 weeks after implantation. Both bisphosphonate coatings increased the pull-out force at both time points, and zoledronate showed a significantly higher pull-out force than pamidronate. To further evaluate the new coating technique we also performed a morphometric study, focusing on the area surrounding the implant. The zoledronate coating resulted in an increased bone density around the screws compared to controls. No pronounced increase was seen around the pamidronate coated screws. Together, the results demonstrate the possibility of obtaining a significant local therapeutic effect with minute amounts of surface immobilized zoledronate.

  • 15.
    Aspenberg, Per
    et al.
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Abtahi, Jahan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Käkkliniken US.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Sandberg, Olof
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Bisphosphonate-induced osteonecrosis of the jaw in a rat model arises first after the bone has become exposed. no primary necrosis in unexposed bone in BONE, vol 50, issue , pp S173-S1732012Ingår i: BONE, Elsevier , 2012, Vol. 50, s. S173-S173Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 16.
    Aspenberg, Per
    et al.
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Abtahi, Jahan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Käkkliniken US.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Sandberg, Olof
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dental implants in a rat model: Bisphosphonate coating improved fixation while systemic treatment caused osteonecrosis in BONE, vol 50, issue , pp S173-S1742012Ingår i: BONE, Elsevier , 2012, Vol. 50, s. S173-S174Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 17.
    Aspenberg, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Targeting RANKL for reduction of bone loss around unstable implants: OPG-Fc compared to alendronate in a model for mechanically induced loosening2011Ingår i: BONE, ISSN 8756-3282, Vol. 48, nr 2, s. 225-230Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Orthopedic joint prostheses may loosen because of localized bone resorption. Despite initial optimism, there are no reports showing that bisphosphonates can stop the progression of prosthetic loosening once it has begun. This might be due to the strong resorptive stimulus, which continuously recruits new osteoclasts. Therefore, we hypothesized that a treatment targeting osteoclast recruitment would be more efficacious than a treatment reducing osteoclast activity. We used a previously described rat model for instability-induced bone resorption, and compared OPG-Fc with alendronate at a clinically relevant or an extreme dose. A titanium plate was osseointegrated at the rat tibial surface. Instability was simulated by a piston, moving perpendicularly to the bone surface. Piston movement induced bone loss via hydrostatic pressure or fluid flow. Rats were randomized to 5 groups (total n = 56), of which 4 were subjected to instability and one was stable. The unstable groups were injected with either high-dose OPG-Fc (10 mg/kg, twice weekly), a high dose of alendronate (20 mu g /kg/day), an extreme dose of alendronate (200 mu g/kg/day) or saline. Significant protection against resorption could only be shown for OPG-Fc and the extreme alendronate dose. Both alendronate doses reduced serum levels of tartrate-resistant acid phosphatase isoform 5b to a similar extent, demonstrating that the lower dose was able to reduce resorption in the normally remodeling skeleton, although not in the osteolytic lesions caused by instability. Osteoclast numbers in the lesion were increased by the lower bisphosphonate dose and reduced by OPG-Fc. The results suggest the possibility of targeting osteoclast recruitment via the RANKL system in patients with impending prosthetic loosening.

  • 18.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Bostrom, Mathias Pg
    Hospital for Special Surgery, New York, NY, USA.
    Yang, Xu
    Hospital for Special Surgery, New York, NY, USA.
    Johansson, Lars
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Edlund, Ulf
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    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, Ortopedicentrum, Ortopedkliniken Linköping.
    Fluid pressure and flow as a cause of bone resorption2010Ingår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 81, nr 4, s. 508-516Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Unstable implants in bone become surrounded by an osteolytic zone. This is seen around loose screws, for example, but may also contribute to prosthetic loosening. Previous animal studies have shown that such zones can be induced by fluctuations in fluid pressure or flow, caused by implant instability. Method To understand the roles of pressure and flow, we describe the 3-dimensional distribution of osteolytic lesions in response to fluid pressure and flow in a previously reported rat model of aseptic loosening. 50 rats had a piston inserted in the proximal tibia, designed to produce 20 local spikes in fluid pressure of a clinically relevant magnitude (700 mmHg) twice a day. The spikes lasted for about 0.3 seconds. After 2 weeks, the pressure was measured in vivo, and the osteolytic lesions induced were studied using micro-CT scans. Results Most bone resorption occurred at pre-existing cavities within the bone in the periphery around the pressurized region, and not under the piston. This region is likely to have a higher fluid flow and less pressure than the area just beneath the piston. The velocity of fluid flow was estimated to be very high (roughly 20 mm/s). Interpretation The localization of the resorptive lesions suggests that high-velocity fluid flow is important for bone resorption induced by instability.

  • 19.
    Linderbäck, Paula
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Wermelin, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Närhi, Timo
    Turku Clinical Biomaterial Centre, The University of Turku, FI-20520 Turku, Finland.
    Tengvall, Pentti
    University of Gothenburg.
    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.
    Weak effect of strontium on early implant fixation in rat tibia2012Ingår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, nr 1, s. 350-356Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Strontium ranelate increases bone mass and is used in the treatment of osteoporosis. Its effects in metaphyseal bone repair are largely unknown. We inserted a stainless steel and a PMMA screw into each tibia of male Sprague-Dawley rats. The animals were fed with ordinary feed (n =40) or with addition of strontium ranelate (800mg/kg/day; n = 20). As a positive control, half of the animals on control feed received alendronate subcutaneously. The pullout force of the stainless steel screws was measured after 4 and 8 weeks, and μCT was used to assess bone formation around the PMMA screws. No significant effects of strontium treatment on pullout force were observed, but animals treated with bisphosphonate showed a doubled pullout force. Strontium improved the microarchitecture of the cancellous bone below the primary spongiosa at the growth plate, but no significant effects were found around the implants. Strontium is known to improve bone density, but it appears that this effect is weak in conjunction with metaphyseal bone repair and early implant fixation.

  • 20.
    Macias, Brandon R.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. 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.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Paradoxical Sost gene expression response to mechanical unloading in metaphyseal bone2013Ingår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 53, nr 2, s. 515-519Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Sost gene encodes Sclerostin, an inhibitor of Wnt-signaling, generally considered a main response gene to mechanical loading in bone. Several papers describe that unloading leads to upregulation of Sost, which in turn may lead to loss of bone. These studies were based on whole bone homogenates or cortical bone. By serendipity, we noted an opposite response to unloading in the proximal rat tibia. Therefore, we hypothesized that Sost-expression in response to changes in mechanical load is bone site specific. less thanbrgreater than less thanbrgreater thanOne hind limb of male, 3 month old rats was unloaded by paralyzing the extensors with Botulinium toxin A (Botox) injections. A series of experiments compared the expression of Sost mRNA in the unloaded and contralateral, loaded limbs, after 3 or 10 days, in metaphyseal cancellous bone, metaphyseal cortical bone, and diaphyseal cortical bone. We also conducted mu CT to confirm changes in bone volume density related to unloading. Sost mRNA expression in the cancellous metaphyseal bone was downregulated almost 2-fold, both 3 days and 10 days after unloading (Pandlt;0.05). A similar tendency was seen in the metaphyseal cortical bone, in which Sost was 1.5-fold downregulated (Pandlt;0.05) after 10 days, but not significantly changed after 3 days. In contrast, diaphyseal cortical Sost expression was instead upregulated 1.4-fold (Pandlt;0.05) following 3-day unloading, while there was no significant change after 10 days. Cancellous bone volume density was 58% lower (Pandlt;0.001, compared to cage controls) in the unloaded limb but not significantly affected in the loaded limb. less thanbrgreater than less thanbrgreater thanThe results suggest that Sost mRNA expression in metaphyseal bone responds to mechanical unloading in an opposite direction to that observed in diaphyseal cortical bone. This proposes a more complex expression pattern for Sost in response to unloading. Therapeutics that target Sclerostin during altered loading conditions may result in local bone mass changes that are difficult to predict.

  • 21.
    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 injury2012Ingår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 83, nr 3, s. 305-310Artikel i tidskrift (Refereegranskat)
    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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