Neural and Physical Niches Orchestrate Skeletal Remodelling and Promote Cartilage Regeneration
type: CreativeWork
description: The skeleton is densely innervated by sympathetic noradrenergic and cholinergic nerve fibres. While several studies suggest the bone-catabolic nature of noradrenergic innervation in decreasing osteoblast activity and promoting osteoclastogenesis, there is little known on the development and function of skeletal cholinergic innervation. Therefore, the first goal of my dissertation research was to elucidate potential secreted factors that promote cholinergic differentiation during postnatal skeletal development, and to examine the function of the cholinergic system in bone using genetic and pharmacological depletion of cholinergic neurons. Treatment of superior cervical ganglion cultures with interleukin-6 (IL-6) for 14 days induced cholinergic, and reduced noradrenergic, gene and protein expression. In vivo studies showed IL-6 expression in developing skeletal muscle cells, and depletion of IL-6 using targeted antibodies and IL-6-deficient mice led to reduced cholinergic innervation in developing long bones. Further, genetic ablation of GDNF family receptor-α2 (Gfra2) induced expression of tumour necrosis factor-alpha converting enzyme (TACE) in neurons, which promotes cleavage of IL-6 receptor leading to enhanced trans-IL-6 signalling, reducing cholinergic trans-differentiation. Therefore, during postnatal life, sprouting sympathetic neurons contact the periosteum and respond to IL-6 secreted by skeletal muscle, resulting in cholinergic differentiation when intrinsic TACE levels are low. Genetic lineage tracing of choline acetyltransferase (ChAT) confirmed dense cholinergic innervation in periosteum and cortical bone, with sparse branches reaching trabecular bone, and labelled bone-lining osteoprogenitors shown to amplify the cholinergic signal to the bone marrow parenchyma. Selective depletion of cholinergic neurons using Gfra2 knockout (Gfra2-/-) mice reduced cortical and trabecular bone mass, bone strength, and bone formation rate. While osteoclast numbers were u…
abstract: The skeleton is densely innervated by sympathetic noradrenergic and cholinergic nerve fibres. While several studies suggest the bone-catabolic nature of noradrenergic innervation in decreasing osteoblast activity and promoting osteoclastogenesis, there is little known on the development and function of skeletal cholinergic innervation. Therefore, the first goal of my dissertation research was to elucidate potential secreted factors that promote cholinergic differentiation during postnatal skeletal development, and to examine the function of the cholinergic system in bone using genetic and pharmacological depletion of cholinergic neurons. Treatment of superior cervical ganglion cultures with interleukin-6 (IL-6) for 14 days induced cholinergic, and reduced noradrenergic, gene and protein expression. In vivo studies showed IL-6 expression in developing skeletal muscle cells, and depletion of IL-6 using targeted antibodies and IL-6-deficient mice led to reduced cholinergic innervation in developing long bones. Further, genetic ablation of GDNF family receptor-α2 (Gfra2) induced expression of tumour necrosis factor-alpha converting enzyme (TACE) in neurons, which promotes cleavage of IL-6 receptor leading to enhanced trans-IL-6 signalling, reducing cholinergic trans-differentiation. Therefore, during postnatal life, sprouting sympathetic neurons contact the periosteum and respond to IL-6 secreted by skeletal muscle, resulting in cholinergic differentiation when intrinsic TACE levels are low. Genetic lineage tracing of choline acetyltransferase (ChAT) confirmed dense cholinergic innervation in periosteum and cortical bone, with sparse branches reaching trabecular bone, and labelled bone-lining osteoprogenitors shown to amplify the cholinergic signal to the bone marrow parenchyma. Selective depletion of cholinergic neurons using Gfra2 knockout (Gfra2-/-) mice reduced cortical and trabecular bone mass, bone strength, and bone formation rate. While osteoclast numbers were u…
author: Gadomski, Stephen
language: eng
keywords: bone marrow stromal cell, bone remodelling, cholinergic, chondrogenesis, fibrin microbead, induced pluripotent stem cell, osteocyte, skeletal stem cell, sympathetic
license: https://www.repository.cam.ac.uk/bitstreams/7f7654e0-438f-4b49-80f2-083aaca85b43/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2023-01-09
date modified: 2026-07-22T22:23:57Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.96557