After discovering that lack of Sost/sclerostin expression is the cause of the 
high bone mass human syndromes Van Buchem disease and sclerosteosis, extensive 
animal experimentation and clinical studies demonstrated that sclerostin plays a 
critical role in bone homeostasis and that its deficiency or pharmacological 
neutralization increases bone formation. Dysregulation of sclerostin expression 
also underlies the pathophysiology of skeletal disorders characterized by loss 
of bone mass, as well as the damaging effects of some cancers in bone. Thus, 
sclerostin has quickly become a promising molecular target for the treatment of 
osteoporosis and other skeletal diseases, and beneficial skeletal outcomes are 
observed in animal studies and clinical trials using neutralizing antibodies 
against sclerostin. However, the anabolic effect of blocking sclerostin 
decreases with time, bone mass accrual is also accompanied by anti-catabolic 
effects, and there is bone loss over time after therapy discontinuation. 
Further, the cellular source of sclerostin in the bone/bone marrow 
microenvironment under physiological and pathological conditions, the pathways 
that regulate sclerostin expression and the mechanisms by which sclerostin 
modulates the activity of osteocytes, osteoblasts, and osteoclasts remain 
unclear. In this review, we highlight the current knowledge on the regulation of 
Sost/sclerotin expression and its mechanism(s) of action, discuss novel 
observations regarding its role in signaling pathways activated by hormones and 
mechanical stimuli in bone, and propose future research needed to understand the 
full potential of therapeutic interventions that modulate Sost/sclerostin 
expression.