Sclerostin actions in bone and metabolic disease.

Sclerostin, a 24 kDa glycoprotein secreted primarily by matrix-embedded osteocytes, plays an essential role in the maintenance of bone mass. Sclerostin acts as a suppressor of bone mass accrual through its inhibitory effects on Wnt/β-catenin signaling, which is most dramatically observed in the rare bone overgrowth conditions associated with SOST gene loss of function in humans and laboratory models. In recent years, a second extra-skeletal function for sclerostin has emerged due to its presence in the circulation and the association between serum levels and metabolic indices. Indeed, genetic and pharmacologic inhibition of sclerostin reduces the accumulation of adipose tissue mass and improves insulin sensitivity in mouse models. In this review, we provide an overview of both the basic science and clinical studies that serve as a rationale for the targeting of sclerostin in the treatment of bone loss and describe pre-clinical research focused on sclerostin's actions as a bone-derived endocrine factor that contributes to the skeleton's influence on systemic metabolism and integrative physiology.