Ralston, Stuart

Salter, Donald

Roberts, Simon Benedict

Wellcome Trust

2018-03-26T11:13:07Z

2018-03-26T11:13:07Z

2018-06-30

Primary osteoarthritis (OA) is a late-onset, degenerative condition of synovial joints, and is the major cause of pain and disability in older persons. OA represents a significant disease burden and focus of research, especially as no disease-modifying therapies exist to manage the condition. The genetic influence to OA is complex and polygenic. The arcOGEN study, the most powerful genome-wide association study yet to investigate OA in humans, identified the 9q33.1 locus to be significantly associated with hip OA in females. TRIM32 lies within the 9q33.1 susceptibility locus and may have strong biological relevance to OA; it encodes a protein with E3 ubiquitin ligase activity. Sanger sequencing of TRIM32 in the youngest 500 female patients with hip OA from the arcOGEN study was performed to identify rare variants in TRIM32 that are associated with OA of the hip in females. Polymorphisms were identified in the proximal promoter, and 3’untranslated regions (3’UTR) of TRIM32 that are disproportionately represented in female patients with hip OA, compared to the control population. In vitro studies identified expression of TRIM32 in human femoral head cartilage; reduced expression of TRIM32 was also demonstrated in femoral head primary articular chondrocytes from patients with hip OA compared to control patients. Trim32 knockout resulted in increased aggrecanolysis in murine femoral head explants. Murine chondrocytes deficient in Trim32 also exhibited increased expression of markers of a mature chondrocyte phenotype in response to anabolic cytokine stimulation, and increased expression of markers of a hypertrophic chondrocyte phenotype upon catabolic cytokine stimulation. In vivo studies of joint degeneration in Trim32 knockout mice demonstrated increased cartilage degradation and tibial epiphyseal bone changes after surgically induced knee joint instability, compared to wild-type mice. Increased cartilage degradation and medial knee subchondral bone changes were also identified upon ageing of Trim32 knockout mice. These results further implicate TRIM32 in the genetic predisposition to OA, and indicate a role for TRIM32 in the joint degeneration evident in OA. These results support the further study of TRIM32 in the pathophysiology of OA and development of novel therapeutic strategies to manage OA.

http://hdl.handle.net/1842/28982

en

The University of Edinburgh

Roberts SB, Wootton E, De Ferrari L, Albagha O, Salter DM. Epigenetics of osteoarticular diseases: recent developments. Rheumatology International. 2015; 35 (8): 1293-1305. PMID: 25812537.

Roberts SB, Borjesson A, Sophocleous A, Salter DM, Ralston SH. Role of Trim32 in osteoarthritis: Trim32-deficient mice develop accelerated knee osteoarthritis after destabilisation of the medial meniscus (DMM) surgery and upon ageing. Osteoarthritis and Cartilage 2016; 24 (Suppl 1): S18.

osteoarthritis

genetics

TRIM32

Investigating new genetic susceptibility loci in osteoarthritis

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy