The <scp>SFRP1</scp> Inhibitor <scp>WAY</scp> ‐316606 Attenuates Osteoclastogenesis Through Dual Modulation of Canonical Wnt Signaling

Osteoporosis, a noteworthy age-related disease induced by imbalanced osteogenesis and osteoclastogenesis, is a serious economic burden on both individuals and society. Small molecule drugs with dual effects on both bone resorption and mineralization are pressingly needed. Secreted frizzled-related protein 1 (SFRP1), a well-known extracellular repressor of canonical Wnt signaling, has been reported to regulate osteogenesis. Global SFRP1 knockout mice show significantly elevated bone mass. Although osteoclasts (OCs) express and secrete SFRP1, the role of SFRP1 produced by OCs in osteoclastogenesis and osteoporosis remains unclear. In this work, the levels of SFRP1 were found to be increased in patients with osteoporosis compared with healthy controls. Pharmacological inhibition of SFRP1 by WAY-316606 (WAY)- attenuated osteoclastogenesis and bone resorption in vitro. The expressions of OC-specific genes were suppressed by the SFRP1 inhibitor, WAY. Mechanistically, both extracellular and intracellular SFRP1 could block activation of the canonical Wnt signaling pathway, and WAY reverse the silent status of canonical Wnt through dual effects, leading to osteoclastogenesis inhibition and osteogenesis promotion. Severe osteopenia was observed in the ovariectomized (OVX) mouse model, and WAY treatment effectively improved the OVX-induced osteoporosis. In summary, this work found that SFRP1 supports OC differentiation and function, which could be attenuated by WAY through dual modulation of canonical Wnt signaling, suggesting its therapeutic potential. &#169; 2021 American Society for Bone and Mineral Research (ASBMR).