Death receptor 3: A regulator of bone turnover\ud and new target for therapy for osteoporosis?
Death receptor 3 (DR3) is a member of the TNFRSF and has one confirmed TNFSF ligand -\ud TNF-like protein 1A (TL1A). Recent studies have suggested a role for DR3/TL1A in\ud osteoclast (OC) and osteoblast (OB) biology. However, the mechanism through which\ud they acted and the consequences in diseases characterised by adverse bone pathology\ud were not investigated. This thesis investigated the role of DR3/TL1A in OC formation and\ud resorptive function (murine and human), diseases characterised by OC hyper-activity and\ud homeostatic OB differentiation and function (murine) using cell culture and molecular\ud biology techniques.\ud DR3/TL1A were demonstrated for the first time to have a direct effect on in vitro OC\ud formation and resorptive function in both murine and human models. DR3 was revealed\ud to be critical for OC resorptive function (murine) while TL1A dose-dependently increased\ud osteoclastogenesis and resorptive function in the human system. Studies into the\ud mechanism identified that DR3/TL1A regulated expression of the chemokines CCL2 and\ud CCL3 as well as the activation of MMP-9. In rheumatoid arthritis patient serum TL1A was\ud significantly increased, with levels linked to the presence of rheumatoid factor and erosive\ud disease. Intriguingly, DR3/TL1A were shown to have no direct significant role in the\ud increased OC activity associated with post-menopausal osteoporosis; DR3 was not\ud detected on patient-derived OC precursors and serum levels of TL1A were not elevated.\ud Analysis of murine osteoprogenitors and OB revealed expression of DR3 and TL1A and\ud suggested a novel autocrine role in OB differentiation. This was supported by the OB\ud mineralisation assay results which demonstrated reduced differentiation, MMP-2 and\ud MMP-9 activation and mineral deposition in DR3ko cultures.\ud The results presented in this thesis identify a novel, complex and multi-factorial role for\ud DR3/TL1A in controlling OC and OB differentiation and function; imbalances in which can\ud lead to the pathogenesis of adverse bone pathology.
Online Research @ Cardiff (http://orca.cf.ac.uk/50191/1/2013CollinsFLPhD.pdf)