Investigating the role of bone and nerve interactions in osteoarthritic pain and pathology

Jones, Ryan 2024. Investigating the role of bone and nerve interactions in osteoarthritic pain and pathology. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Bone is intricately coupled with the sensory nervous system and one of the only joint tissues known to show changes that correlate with patient pain in Osteoarthritis. Profound neuroplasticity has been shown in osteoarthritic subchondral bone and is associated with pain responses. Under normal circumstances bone osteoblast and osteocyte cells inhibit neural invasion. However, mechanisms underlying the loss of this inhibition in osteoarthritic subchondral bone are unknown. Osteocytes are mechanically sensitive and orchestrate bone responses by coordinating the activity of other bone cells. This study demonstrates the neural signalling capability of osteocyte, how this signalling is modified by pathological stimulation and differs between the sexes. This thesis presents the mediator Sema3A as a potential mediator of these effects. Sema3A acts as an anabolic agent in bone, promoting and inhibiting the differentiation and activity of osteoblasts and osteoclasts, respectively. Sema3A inhibits sensory nerve, blood vessel and immune cell differentiation and invasion and hyperpolarises neurons and restricts their activation. The Sema3 pathway is differentially regulated in human osteoarthritis patient subchondral bone. Using novel methodology this thesis describes how pathological load inhibits the nociceptor repulsive capability of osteocyte cultures and induces nociceptor invasion as displayed in osteoarthritic subchondral bone. Pathological mechanical loading of osteocytes in vitro downregulates Sema3A signalling and the downregulation of Sema3A is correlated with the branching and invasion of cultured nociceptors. Synovial Sema3A concentrations are also inversely correlated to osteoarthritis patient joint overloading and pain. This thesis reveals Sema3A as a biological mediator that links pathological biomechanical loading to neural changes known to evoke pain in osteoarthritis.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	11 April 2025
Last Modified:	14 Apr 2025 10:41
URI:	https://orca.cardiff.ac.uk/id/eprint/177612

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