The Role of the a10 Integrin Subunit in Bone Structure and Function

The alO~1 integrin is a major collagen-binding integrin expressed by gro~ plate chondrocytes during skeletal development. alO~l expressi~n has also been detected'in the perichondrium, heart valves, skeletal muscle fascia, the sUrface of ligaments, and more recently in bone endosteal lining and osteoblasts lining trabecular bone.: It has previously been shown that alO deficient mice (alO'I) display no more than a mild phenotype, with only a slight, time progressive shortening of the long bones (7-10%). This is accompanied by modest growth plate abnormalities characterised by a reduction in the height of the hypertrophic zone, cell shape and organisation changes in the proliferative zone, suggesting an important role for a 1O~1 integrin in endochondral ossification. The studies described in this thesis tested the following hypotheses: i) that the alO integrin subunit impacts upon the development and maintenance of cortical and tibial bone structure; ii) that alO,7- mice exhibit a diminished tibial response to identical levels of applied mechanical strain compared to their age-matched wild-type controls; iii) that the ato integrin subunit has direct roles in determining osteoblast and osteoclast behaviour and iv) that the lack of the alO integrin subunit results in a dis-regulation of bone formation and bone resorption, which is a result of a failure in osteoblast/osteoclast coupling. Analysis ofthe appendicular skeleton in a cross-section (young, adult and old males and females) of al0-1 - mice via JlCT revealed significant reductions in bone volume in both the cortical and trabecular compartments which became less apparent with ageing. In vivo mechanical loading of the tibia revealed that despite the reduction in bone volume, a10-1- mice have an enhanced response to identical levels of applied strain at all ages and genders, with the exception of adult female alO-f - mice. In vitro experiments using long bone derived alO-f- osteoblasts revealed an enhanced basal proliferation rate and a diminished ability of a10-1 - osteoblasts to differentiate in response to differentiation factors. These fmdings were replicated in normal primary osteoblasts using an a10 blocking antibody. Osteoclast behaviour was also shown to be modified, with increased levels of osteoclastogenesis observed in the absence ofthe a 10 integrin subunit. ELISA analysis ofserum bone turnover markers suggested that the aID integrin subunit restricts the rate of decline in osteoblast formation associated with maturation, but facilitates decline in osteoclast resorption, associated with an osteoblastic compensation for the apparent increased osteoclast formation and resorption. These results have revealed the importance ofthe aID integrin subunit in the attainment and maintenance of bone mass, with specific effects on osteoblast proliferation and differentiation, and control of osteoclast function. Together these fmdings highlight the potential of the aID integrin subunit to be a novel target for therapeutic modulation in the treatment of metabolic bone diseases such as osteoporosis.EThOS - Electronic Theses Online ServiceGBUnited Kingdo