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Ontogeny of sensory and autonomic nerves in the developing mouse skeleton
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
2013 (English)In: Autonomic Neuroscience: Basic & Clinical, ISSN 1566-0702, E-ISSN 1872-7484, Vol. 177, no 2, 237-243 p.Article in journal (Refereed) Published
Abstract [en]

Background: Bone innervation is implicated in bone modeling and remodeling. This study investigates skeletal nerve development in embryonic and newborn mice, focusing on sensory and autonomic nerves and their temporal occurrence. Materials and methods: The ontogeny of innervation and angiogenesis in the hindlimb skeleton of mice was studied from embryonic day (E) 15 to postnatal day (P) 20. Neuronal tissue was immunohistochemically labeled for detection of growth associated protein 43 (GAP-43), protein gene product 9.5 (PGP 9.5), calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), and neuropeptide Y (NPY). Vascular endothelium was labeled for platelet endothelium cell adhesion molecule-1 (PECAM-1). Morphology was evaluated with hematoxylin and eosin staining. Results: GAP-43, PGP 9.5, CGRP, and PECAM-1 were all present at E 15, adjacent to areas with high osteogenic and chondrogenic activity. In the primary ossification centers, GAP-43 was found at E 15, PGP 9.5 at E 17, CGRP at E 19, and NPY at P4. The same time lag in appearance was observed in the secondary ossification centers. The covering capillary network was initially dense, but became mature and sparse from P 12 onwards. Conclusion: A functional nerve supply co-localized with a rich capillary network is seen early in the developing mouse skeleton, especially in areas with high osteogenic activity. Sensory innervation occurs prior to partus, while autonomic innervation (revealed by the presence of NPY and TH) is established post partum. The findings indicate a time-related development of nerves with different qualities, according to skeletal development.

Place, publisher, year, edition, pages
2013. Vol. 177, no 2, 237-243 p.
Keyword [en]
Immunohistochemistry-bone, Calcitonin gene-related peptide, Neuropeptide Y, Tyrosine hydroxylase, PECAM-1, Skeletal development, Mouse bone innervation
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-99438DOI: 10.1016/j.autneu.2013.05.005ISI: 000325665700024OAI: oai:DiVA.org:uu-99438DiVA: diva2:207911
Available from: 2009-03-13 Created: 2009-03-13 Last updated: 2016-02-17Bibliographically 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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Sisask, GregorSilfverswärd, Carl-JohanBjurholm, Anders
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