BMP-7: role and regulation in osteoarthritis

Bennett, Louise Agnes (2017) BMP-7: role and regulation in osteoarthritis. PhD thesis, University of Glasgow.

Abstract

Osteoarthritis (OA) is a disease characterised by changes in the structure and function of articular joints, leading to pain and loss of mobility. Bone Morphogenetic protein 7 (BMP-7), a member of the transforming growth factor β superfamily, has been shown to promote anabolic events within articular cartilage, and confer protection from OA associated destruction in a number of animal models. It has been shown that a disease-associated loss of BMP-7 in OA may contribute to the joint destruction. The mechanism associated with the loss of BMP-7 has yet to be fully elucidated. Recently, small non-coding RNAs (microRNAs) that participate in post-transcriptional gene regulation, have been identified as a potential dysregulated mechanisms in OA. It was therefore hypothesised that disease-associated alterations in these microRNAs could lead to subsequent changes in the expression of BMP-7 and its signalling family. The aims of this thesis were to investigate the expression of BMP-7 and other associated BMP signalling molecules and identify any microRNAs that may regulate these transcripts. Furthermore, the study aimed to elucidate the molecular mechanisms by which BMP-7 is able to confer protection in cartilage.

The studies presented in this thesis show that both articular chondrocytes and the synovial membrane can express very low levels of BMP-7 transcript in a subset of patients. In juxtaposition, protein can be clearly detected in both articular chondrocytes and synovial membrane. Interrogation of the BMP-7 signalling family transcripts revealed that all members are detectable in OA cartilage. This expression was independent of the eroded nature of the cartilage. Evaluation of the circulating microRNAs that were predicted to target the BMP-7 pathway revealed that several miRNAs (including miR24-3p) were altered in the plasma of OA patients. Interestingly, miR24-3p was able to target BMP receptors ALK2 and BMPR1B. Moreover, there was a significant negative correlation between the expression of miR24-3p and the ALK2 receptor in OA patients. Thus suggesting there is a role for this miRNA in the negative regulation of BMP-7 signalling in OA cartilage.

To complement the work evaluating the endogenous signalling pathway, studies were also undertaken to investigate the impact of exogenous BMP-7 stimulation on chondrocytes. BMP-7 was able to promote its own transcriptional expression in a patient specific manner and induce expression of IL-1β in all of the donors investigated. In addition to the induction of IL-1β, BMP-7 was also able to up-regulated the IL-1β antagonist, IL-1Ra. Taken together this data suggests a role for BMP-7 in the regulation of the inflammatory mediator IL-1β. Finally, BMP-7 was able to up-regulate several pro-inflammatory cytokines and chemokines in both primary OA chondrocytes and in vitro differentiated macrophages.

In summation, the work presented in this thesis suggests that BMP-7 may be contributing to the promotion of inflammation and subsequent repair as part of the cartilage homeostatic mechanisms. Further to this, miR24 has been highlighted as a regulator of cartilage homeostasis via the direct targeting of ALK2. Changes in the expression of this miRNA over the course of OA disease progression may be involved in driving disease pathogenesis. Therefore understanding the targets for this disease-associated miRNA may help in the development of disease modifying therapies.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Osteoarthritis, microRNA, BMP-7.
• Subjects: Q Science > Q Science (General); Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Supervisor's Name: Goodyear, Dr. Carl S., Kurowska-Stolarska, Dr. Mariola and Blyth, Mr. Mark
• Date of Award: 2017
• Depositing User: Dr Louise Agnes Bennett
• Unique ID: glathesis:2017-8171
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 May 2017 15:39
• Last Modified: 09 Jun 2017 07:35
• URI: https://theses.gla.ac.uk/id/eprint/8171