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Sensory nerve fibres, neuropeptides and cartilage: Experimental studies in the rat
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During development, maintenance and repair after injury, reciprocal interactions occur between the peripheral nervous system and the target tissues. In the Papers presented in this thesis, different aspects of such netvetarget influences between peripheral nerve fibres and skeletal tissues dtuing development and repair have been investigated in the rat. Developing rat cartilaginous bone primordia have a richly innervated and vascularised perichondriwn. In addition, larger bones exhibit cartilage canals containing blood vessels and putative sensory nerve fibres. Tills evoked the question if there is a nervous regulation of skeletal development. Denervation of the hind paws of young rats resulted in a deficient length growth but had no influence on the progress of secondary ossification. Since growth is mainly due to events in cartilage, cartilage projecting sensory neurones were identified and examined. Sensory neurones projecting to the rat cartilaginous distal femoral epiphyses were located mainly in the dorsal root ganglia (DRG) L3 and L4 and exhibited small or medium-sized diameters. A large proportion of these neurones contained the neuropeptides CGRP and/or SP. However, application of CGRP to cartilage explants in vitro did not stimulate the chondrocytes in terms of an elevation of the level of cyclic AMP. Another possibility would be that the neuropeptides affect the developmental growth of bone and chondrocytes indirectly via effects on the blood vessels. Experiments .involving tracing as above and eo-culture of labelled DRG neurones and perichondrial cells in combination with immunohistochenllstty or electrophysiology showed that the traced cultured neurones contained CGRP and/or SPin in vivo-like proportions and that most of the cartilage-projecting neurones were proton sensitive, This prompted the suggestion that the nerve fibres in the perichondrium and in cartilage canals might release CGRP and SP in response to local tissue acidosis, thereby promoting tissue homeostasis by monitoring the balance between vascular supply and metabolic load and by influencing angiogenesis and blood flow. Subsequently, possible target influences on the local presence of perichondrial sensory nerve fibres were investigated. Application of inflammation related cytokines (IL-1ß, IL-6 and LIF) affected sensory neurones eo-cultured with perichondrium- or skin-derived fibroblast-like cells in terms of survival and neurite growth. These effects were strongly influenced by the origin of the target cells. Finally, experiments using the adult rat patella showed that osteochondral defects heal spontaneously but incompletely and that healing is not accompanied by an increase of local nerve fibres at the times examined. In conclusion, the present results indicate that cartilagerelated sensory nerve fibres influence skeletal growth, that a high proportion of these neurones contain CGRP and SP, that CGRP does not activate chondrocytes in cartilage slices, that many cartilage related sensory nerve fibres are proton-sensitive· and likely have a vasoregulatory role, that inflammatory mediators have distinct effects on sensory neurones eo-cultivated with perichondrial cells and that healing of an osteochondral defect in the rat patella does not involve a local increase of cartilage-related nerve fibres.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2001. , 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 712
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25639Local ID: 10014ISBN: 91-7373-141-1 OAI: oai:DiVA.org:liu-25639DiVA: diva2:246187
Public defence
2001-12-14, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-08-23Bibliographically approved
List of papers
1. The developmental skeletal growth in the rat foot is reduced after denervation
Open this publication in new window or tab >>The developmental skeletal growth in the rat foot is reduced after denervation
1997 (English)In: Anatomy and Embryology, ISSN 0340-2061, E-ISSN 1432-0568, Vol. 195, no 6, 531-538 p.Article in journal (Refereed) Published
Abstract [en]

It has long been known that bone is innervated. In recent years it has been suggested that the local nerves may influence the growth and metabolism of bone by way of neuropeptides. The transient local presence of nerve-containing cartilage canals just before formation of secondary ossification centres in rat knee epiphyses seems to support that view. The purpose of the present study was to see if denervation affects the developmental growth of metatarsal bones in the rat hindfoot. We made sciatic and femoral neurectomies in 7- day-old rat pups and examined the hindfeet at various times after surgery. Immunohistochemical analysis showed that denervation was complete. Radiographic examination revealed that the metatarsal bones were significantly shorter in denervated hindfeet 30 days after denervation (average relative shortening 9.9±2.3%). Measurements of total foot length showed that denervated feet were subnormally sized already five days postoperatively, before the onset of secondary ossification. The timing of the latter was not affected by denervation. Control rats subjected to tenotomies exhibited normal metatarsal bone lengths. On the basis of these results we suggest that the local nerves may influence the growth of immature bones but do not affect secondary ossification.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80296 (URN)10.1007/s004290050073 (DOI)9193728 (PubMedID)
Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2017-12-07Bibliographically approved
2. Retrograde tracing and neuropeptide immunohistochemistry of sensory neurones projecting to the cartilaginous distal femoral epiphysis of young rats
Open this publication in new window or tab >>Retrograde tracing and neuropeptide immunohistochemistry of sensory neurones projecting to the cartilaginous distal femoral epiphysis of young rats
2000 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 299, no 2, 193-200 p.Article in journal (Refereed) Published
Abstract [en]

Although cartilage is considered to be devoid of innervation, axons occur in the perichondrium and during development in cartilage canals, thereby having a relatively close spatial relationship to chondroblasts and chondrocytes. The present study locates the source of the sensory innervation of the femoral cartilaginous epiphyses of young rats and investigates whether the neuropeptide calcitonin gene-related peptide (CGRP) can influence chondrocytes. Retrograde tracing from the distal femoral epiphysis of young rats with Fast Blue (FB) showed labelled neuronal profiles in the L2-L5 dorsal root ganglia. Sample countings indicated that 50% of the FB-labelled neuronal profiles were located at the L3 level and 25% at the L4 level. The labelled neurones had diameters of 15-40 µm, with a peak at 25-30 µm. Immunohistochemistry showed that about 50% of the FB-labelled profiles contained CGRP. Together with the finding that CGRP influences bone cells to generate the second messenger cAMP, this result suggested the hypothesis that chondrocytes might be similarly influenced by CGRP. However, stimulation of cartilage slices with CGRP in vitro followed by an assay of the cAMP content did not provide support for this hypothesis. We conclude that primary sensory neurones containing CGRP project to the perichondrium and to cartilage canals of growing cartilage, and that exogenous CGRP does not elevate the cAMP content of cartilage slices in vitro.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24999 (URN)10.1007/s004410050017 (DOI)9419 (Local ID)9419 (Archive number)9419 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
3. Neuropeptide content and physiological properties of rat cartilage-projecting sensory neurones co-cultured with perichondrial cells
Open this publication in new window or tab >>Neuropeptide content and physiological properties of rat cartilage-projecting sensory neurones co-cultured with perichondrial cells
2001 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 315, no 3, 141-144 p.Article in journal (Refereed) Published
Abstract [en]

In young rats the cartilaginous epiphyses forming the knee joint are supplied with blood vessels and peptidergic sensory nerve fibres through the perichondrium and cartilage canals. In the present study we show that cartilage-related dorsal root ganglion neurones co-cultured with perichondrial cells develop extensive neurite trees and express calcitonin gene-related peptide (CGRP) and substance P (SP) in in vivo-like proportions using retrograde tracing and immunohistochemistry. Moreover, whole cell patch clamp recordings from these cells showed that the majority is depolarised by application of H+-ions. These results are compatible with the hypothesis that a local imbalance of blood flow and metabolism during normal skeletal maturation may cause tissue acidosis eliciting release of CGRP/SP from sensory nerve endings.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24996 (URN)10.1016/S0304-3940(01)02353-9 (DOI)9416 (Local ID)9416 (Archive number)9416 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
4. Effects of IL-1β, IL-6 or LIF on rat sensory neurons co-cultured with fibroblast-like cells
Open this publication in new window or tab >>Effects of IL-1β, IL-6 or LIF on rat sensory neurons co-cultured with fibroblast-like cells
2002 (English)In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 67, no 2, 255-263 p.Article in journal (Refereed) Published
Abstract [en]

Inflammation may affect the local presence of sensory nerve fibers in situ and inflammatory mediators influence sensory neurons in vitro. In the present study we have investigated effects of the cytokines interleukin-1β (IL-1β, interleukin-6 (IL-6), and leukemia inhibitory factor (LIF) on survival of and neurite growth from neonatal rat sensory neurons co-cultured with fibroblast-like cells prepared from neonatal rat skin (sFLCs) or perichondrium (pFLCs). The results showed that both FLC types expressed receptors for all three cytokines. Five ng/ml of either cytokine, but not lower or higher concentrations, supported survival of DRG neurons co-cultured with sFLCs. Neuronal survival was also enhanced by addition of the soluble IL-6 receptor (rsIL-6R) with or without IL-6. In co-cultures with pFLCs neuronal survival was promoted by IL-6, increasing with cytokine concentration. Addition of rsIL-6R without IL-6 did also stimulate neuronal survival. The growth of neurites from DRG neurons co-cultured with sFLCs was stimulated by 0.5 ng/ml LIF, unaffected by 5 ng/ml LIF and inhibited by 50 ng/ml LIF. Considering DRG neurons co-cultured with pFLCs, 50 ng/ml of either of the three cytokines, as well as rsIL-6R conditioned medium, stimulated neurite outgrowth. Some of the cytokine effects observed were reduced by application of antibodies against nerve growth factor (NGF). We conclude that that the cytokines examined affect DRG neurons in terms of survival or neuritogenesis, that the effects are influenced by cytokine concentration and the origin of the FLCs and that some of the effects are indirect, probably being mediated by factors released from FLCs.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24998 (URN)10.1002/jnr.10092 (DOI)9418 (Local ID)9418 (Archive number)9418 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
5. Does healing of an osteochondral defect with or without a periosteal autograft involve a local sprouting of nerve fibres?: An experimental study on the rat patella
Open this publication in new window or tab >>Does healing of an osteochondral defect with or without a periosteal autograft involve a local sprouting of nerve fibres?: An experimental study on the rat patella
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Repair of articular cartilage is an important clinical problem. Availability of chondrogenic stem cells has been pointed out as one key factor in cartilage repair and application of periosteal autografts has been used clinically to improve healing. In addition, neuropeptide containing nerve fibres may contribute to healing by stimulating cell proliferation and/or differentiation. In the rat, peptidergic nerve fibres invade the callus formation during fracture healing and peptidergic nerve fibres are abundant in cartilage related connective tissue during skeletal development in young mammals. The purposes of the present study were to evaluate healing of an experimental full thickness osteochondral defect in the rat patella with and without application of a periosteal autograft, and to find out if a local nerve sprouting is part of the healing process. Osteochondral healing was evaluated with a histological score and the presence of nerve fiber profiles in relation to the defect was assessed by protein gene product 9.5 immunohistochemistry. The results showed (i) that osteochondral defects in the rat patella heal spontaneously but incompletely, (ii) that healing consistently is less satisfactory with application of a periosteal autograft than without and (iii) that healing is not accompanied by nerve fibre sprouting.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80302 (URN)
Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2012-08-23Bibliographically approved

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