Inhibition of NFAT increases osteoblast differentiation by increasing Fra-2 expression

Bone loss and osteoporosis are major public health problems in the elderly. With longer life expectancy in the USA, the number of people that will develop age-related bone loss and osteoporosis is expected to rise to over 61 million by 2020. Osteoblast differentiation is a crucial aspect of bone formation and remodeling, a process that is severely compromised in osteoporosis. Almost all the FDA-approved treatments for building healthier bones, excluding PTH, do not address the decrease in osteoblast differentiation that is seen in osteoporosis and are designed to target osteoclasts and bone resorption. The purpose of this study is to examine the effects of cyclosporine A (CsA) on osteoblast differentiation and elucidate its mechanism of action. CsA, an immunosuppressive agent, is known to cause osteopenia in post-transplantation patients as a result of inhibiting calcineurin and NFAT signaling. The reported effects of CsA on bone are contradictory both in human and animal studies with a common consensus that CsA causes a high turnover bone loss due to an increase in both osteoclast and osteoblast differentiation in vivo. Despite this important observation, almost all studies addressing the effects of CsA on bone have focused on the role of Cn/NFAT on osteoclasts.