The effects of glyceryl trinitrate and ovariectomy on femoro-tibial articular cartilage, synovium and subchondral bone in normal and osteoarthritic ewes

Martin Andrew Cake

Nitric oxide (NO) alters chondrocyte metabolism, and is thought to be a key catabolic mediator in osteoarthritis. NO is also an important modifier of bone metabolism, and may partially mediate the bone-sparing effects of oestrogen. Oestrogen has also been linked to the modulation of osteoarthritis, though its role is not clear. The aim of this study was to examine the structural and metabolic effects of ovariectomy and the NO donor glyceryl trinitrate (GTN) on (1) normal ovine femoro-tibial joint tissues, and (2) the progression of joint lesions in the established ovine meniscectomy model of osteoarthritis. Preliminary investigations tested a novel computer-assisted histomorphometric method of assessing osteochondral changes post-meniscectomy, in a trial of a putative disease-modifying osteoarthritis compound. Quantitative assessment revealed a subtle protective effect not evident by qualitative methods. These techniques were then used to test the experimental hypotheses in a combined trial involving 48 aged ewes, variously subjected to ovariectomy, bilateral lateral meniscectomy, and/or topical GTN therapy. At six months, joint tissues were analysed using histology, histomorphometry, dynamic biomechanical testing, serum markers, bone densitometry, and tissue culture of synovial fibroblasts and explants of cartilage and bone. Ovariectomy modified cartilage structure and chondrocyte metabolism, and induced subchondral bone remodelling. Prior ovariectomy altered the development of OA lesions post-meniscectomy, producing thicker but biomechanically inferior cartilage and elevated metabolic activity in subchondral bone. GTN treatment of normal sheep induced thinner, structurally-altered cartilage in normal sheep, and accentuated cartilage and subchondral bone lesions post-meniscectomy. These results support an important homeostatic role for oestrogen in joint tissues, and show that GTN, a commonly used angina therapy, can induce structural alterations in joint tissues and potentially accelerate the progression of concurrent OA. Results also advance understanding of the role of synovial and subchondral bone changes in the pathogenesis of this OA model.

The effects of glyceryl trinitrate and ovariectomy on femoro-tibial articular cartilage, synovium and subchondral bone in normal and osteoarthritic ewes

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