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Ontogeny of sensory nerves in the developing skeleton
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pediatrics. (Kreicbergs - Bjurholm)
Karolinska institutet, kir. vetenskaper. (Kreicbergs - Bjurholm)
Karolinska institutet, kir. vetenskaper. (Kreicbergs - Bjurholm)
1995 (English)In: Anatomical Record, ISSN 0003-276X, E-ISSN 1097-0185, Vol. 243, no 2, 234-240 p.Article in journal (Refereed) Published
Abstract [en]

Background: Previous studies have shown that the neuropeptide calcitonin gene-related peptide (CGRP) have an influence on osteoclastic bone resorption and that CGRP and substance P (SP), both wellknown markers for sensory neurons, behave as growth factors.Materials and Methods: The ontogeny of the sensory nerves in the hindlimb skeleton of the rat was studied from gestational day (GD) 15 to neonatal day (ND) 24 by immunohistochemistry. Neurofilaments and nerve terminals were labelled with protein gene-product 9.5 (PGP 9.5) and synaptophycin (SYN) respectively.Results: PGP 9.5 appeared at GD 15 and SYN at GD 19, both in the perichondrial tissue of the long bones. One week later, at ND 4 nerve fibre, immunoreactive to PGP 9.5 and SYN were observed within the bone organ. Sensory nerves, indicated by CGRP and SP, were first discerned at GD 18-19 in the periosteal tissue of the diaphyseal and metaphseal regions and in the bone organ at ND 4. Approximately at ND 6, vascular as well as non-vascular nerves extended into the metaphyses and at ND 8 into the epiphyses, concomitant with the first signs of mineralization.Conclusions: The study shows that a functional sensory nerve supply of the developing bone organ occurs immediatly prior to partus, apparently parallel with an increasing mineralization. The combined findings may indicate a sensory influence on developmental processes in the skeleton

Place, publisher, year, edition, pages
1995. Vol. 243, no 2, 234-240 p.
Keyword [en]
Immunohistochemistry, Substance P, Calcitonin gene-related peptide, Rat bone innervation, Skeletal development
National Category
Surgery Cell and Molecular Biology
URN: urn:nbn:se:uu:diva-99431DOI: 10.1002/ar.1092430210PubMedID: 8554179OAI: oai:DiVA.org:uu-99431DiVA: diva2:207907
Available from: 2009-03-13 Created: 2009-03-13 Last updated: 2010-07-08Bibliographically approved
In thesis
1. Bone Development and the Nervous System
Open this publication in new window or tab >>Bone Development and the Nervous System
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Innervation of bone influence bone modeling, growth and remodeling. Pro-inflammatory cytokines released after tissue trauma are recognized as neurotrophic factors as well as factors influencing bone formation. The Wnt signaling pathway, essential for cell migration during embryogenesis is found to influence bone formation during fracture healing. Alterations in growth and bone formation are seen in denervating disorders and in manipulated Wnt signaling. The aim of the present thesis was to study; sensory and autonomic innervation in the developing skeleton in rats and mice, a possible influence on bone formation in IL-4 and IL-13 depleted mice, and fracture healing in altered Wnt signaling by glycogen synthase-3β inhibition in rats.

Bone innervation with sensory and autonomic nerves in modeling and growth follows a predictable and reproducible pattern both in the rat and in the mouse with sensory nerves occurring prior to autonomic nerves in areas with high chondrogenic and osteogenic activity. The time lag in occurrence between sensory and autonomic nerves indicates the importance of developmental timing between different nerve qualities in skeletal ontogeny. These findings give substantial morphologic support for important regulatory effects by the nervous system on bone development.

Depletion of the anti-inflammatory cytokines IL-4 and IL-13 production in mice resulted in an inhibited autonomic innervation and lack of implant capillary ingrowth, studied by DXBM implants. In fracture healing no differences between IL-4/13 knockout mice and wild type mice were found concerning fracture callus parameters, biomechanical properties or histology except that sensory and autonomic nerves were found in the bone marrow in knockout mice but not in wild type mice.

An altered canonical Wnt signaling was achieved by the GSK-3β inhibitor AR28. The increase in cytoplasmic β-catenin, due to inhibited degradation, resulted in a remarkable anabolic effect both on the fractured bone and on fracture healing. The histological analysis showed that the fractures healed without the usual formation of fibro-cartilage callus. This finding suggests that inhibition of GSK-3β inhibits the differentiation of chondrocytes and instead promotes the differentiation of mesenchymal progenitor cells into osteogenic cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 54 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 439
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-99443 (URN)978-91-554-7468-3 (ISBN)
Public defence
2009-04-24, Rosénsalen, Ingång 95/96, Akademiska barnsjukhuset, Uppsala, 09:00 (Swedish)
Available from: 2009-04-03 Created: 2009-03-13 Last updated: 2016-05-30Bibliographically approved

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