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The Development of Autonomic Innervation in Bone and Joints of the Rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
1996 (English)In: Journal of the Autonomic Nervous System, ISSN 0165-1838, Vol. 59, no 1-2, 27-33 p.Article in journal (Refereed) Published
Abstract [en]

The development of autonomic nerves in the hindlimb skeleton, was studied in rats from gestational day (G) 15 to postnatal day (P) 24 by immunoreactivity to neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). Control labelling with antisera to neurofilaments, protein gene-product 9.5 (PGP 9.5), and nerve terminals, synaptophysin (SYN), showed nerve fibres at G15 and nerve terminals at G19 in the perichondrial tissue. From P4, nerve fibres and terminals were observed within the bone organ. Noradrenergic sympathetic nerves, containing NPY, were first discerned at birth, G21, in the perichondrial tissue and within the bone organ at P4. Autonomic cholinergic nerve fibres, indicated by immunoreactivity to VIP, exhibited a similar temporal and regional occurrence. The diaphyseal parts were first supplied with autonomic nerves at P4. The nerve fibres extended into the metaphyses at P6-8 and finally into the epiphyses at P10, concomitant with the first signs of mineralization. Vascular as well as non-vascular nerve fibres were seen. The study shows that developing bone organ is supplied with autonomic nerves from birth, and the the growth of nerves parallels the mineralisation process. Previous studies have demonstrated that NPY potently inhibits parathyroid hormone (PTH) induced effects on osteoblastic bone cells and that VIP is a strong inductor of bone resorption. NPY and VIP also exert vasoregulatory effects. The combined findings suggest an autonomic influence on bone development.

Place, publisher, year, edition, pages
1996. Vol. 59, no 1-2, 27-33 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-58779DOI: 10.1016/0165-1838(95)00139-5PubMedID: 8816362OAI: oai:DiVA.org:uu-58779DiVA: diva2:86688
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2016-05-30Bibliographically 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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