Agu Tamm, MD, PhD, DMSci, Professor, Department of Internal Medicine, University of Tartu
Kalle Kisand, MD, PhD, Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu
Opponent: Kari Pulkki, MD, PhD, FEBMB, Professor, Department of Clinical Chemistry (Laboratory Medicine),
School of Medicine University of Eastern Finland, Kuopio,
Finland Eastern Finland Laboratory Centre
Osteoarthritis (OA) is the most common arthritic disorder, with a large number of environmental and genetic risk factors. Genetic factors have been shown to influence the dynamics and outcomes of OA, as have other OA risk factors. Currently, OA is recognised as a form of arthritis with an inflammatory component, which involves all of the joint tissues. The global burden of the disease and lack of definitive treatment, as well insufficient knowledge of several pathogenetic steps, ensure the importance of genetic research in OA. Comprehensive consideration of promising candidate genes on the mRNA and protein levels could improve our current knowledge of the disease. The aims of the present study were to perform an analysis of two OA candidate genes-ADAM12 (disintegrin and metalloproteinase domain 12) and CILP (cartilage intermediate layer protein)-on DNA-RNA-protein levels in radiographic knee OA (rKOA). The study consisted of a population-based cohort (N=437) and subjects undergoing arthroscopy (N=91), aged 32-60. The current study demonstrated that ADAM12 is associated with rKOA processes at different levels (gene and protein).
Polymorphisms of the ADAM12 gene carried the risk of rKOA. In males and females rKOA risk was associated with different variants. In both genders the risk was associated only with osteophytosis. The protein product of the ADAM12 gene (ADAM12-S) was found at higher concentrations in the late stages of the disease. The expression of ADAM12 mRNA and protein in synovia was up-regulated during synovial inflammation, especially in fibrosis.
CILP, which is thought to be a specific cartilage biomarker, was found in synovia at the mRNA and protein levels, suggesting that synovia may be an additional source of CILP production. Similarly to ADAM12, the synovial expression of CILP mRNA was found to be up-regulated in fibrotic samples. Moreover, CILP mRNA expression was down-regulated in subjects with advanced stages of joint space narrowing. Both genes demonstrated gender-specific effects on rKOA risk and synovial fibrogenesis.
The present study establishes the association of ADAM12 and CILP genes with different aspects of KOA pathogenesis, suggesting involvement of the ADAM12 gene in bone remodelling (osteophytosis), as well the role of ADAM12 and CILP genes in the development of synovial fibrosis.