Grant: Project Grant

Osteoporosis is a common and debilitating disorder of bone fragility in aging populations, which is associated with increased fracture rates. In women, the incidence of osteoporosis increases markedly following menopause. As estrogen promotes bone health, it is the postmenopausal loss of estrogen that is usually linked to osteoporosis. Indeed, many therapies target the estrogen receptor to prevent or treat postmenopausal osteoporosis. Recent observations over the past decade challenge this current dogma, attributing bone loss to the actions of follicle-stimulating hormone (FSH) from the pituitary gland. Estrogen and FSH levels in the bloodstream are tightly linked as FSH stimulates the ovaries to make estrogen. When estrogen levels fall at menopause, FSH levels rise, ostensibly to stimulate more estrogen production. However, the ovaries lack the ability to produce estrogen at this stage of life. Therefore, postmenopausal women have both low estrogen and high FSH, and some researchers have recently argued that it is the elevated FSH that is driving bone loss. In support of their view, they identified receptors for FSH on osteoclast cells in the bone. The normal function of osteoclasts is to degrade bone and FSH has been argued to increase osteoclast activity, and therefore bone loss. As a result of these observations, efforts are being made to develop inhibitors of FSH to treat bone loss in postmenopausal women. This new approach is highly controversial as many investigators question whether previous studies on FSH in bone physiology were correctly interpreted. Here, we propose to resolve this controversy using mouse models unique to our research team. The results of our work will definitely establish whether or not FSH regulates bone.