Figure 1.

Physiological role of osteocytes and Scl and potential mechanism of action of Scl-Ab in BM microenvironment. (A) Unloading conditions induce the production of high Scl levels which, in turn, promote the production of RANKL and decrease OPG with consequent increased RANKL/OPG ratio, osteoclastogenesis, and enhanced bone resorption. Another possible triggering event of RANKL release in BM microenvironment is the osteocyte apoptosis. Simultaneously, high Scl inhibits Wnt signaling and osteoblast formation. (B) Mechanical loading and other factors, such as PTH and estrogens, suppress Scl expression with the consequent induction of Wnt signaling and enhanced bone formation. The production of high levels of OPG and the reduction of RANKL production lead to the suppression of resorption-associated activities. (C) Scl inhibition stimulates bone formation and reduces bone resorption by different mechanisms. Firstly, by blocking the binding between Scl and LRP5/6, Scl-Ab activates a set of Wnt target genes associated with bone formation and resorption (Wisp and Twist) and increased expression of extracellular matrix proteins, such as osteocalcin. The increased of Twist, an inhibitor of bone formation, limits the early response to Scl inhibition, whereas Wisp, a negative bone resorption, sustains the anti-osteoclastogenic activity. The feedback mechanisms following Scl inhibition, is associated with increased levels of Wnt antagonist to attenuate the bone-forming response and prevent excessive bone accrual. Although the anti-resorptive activity is demonstrated in animal studies and in clinical trials, the regulation of osteoclastogenic factors, such as RANKL and OPG, is not clearly and need to be elucidated in further studies. See text for details.