Anabolic effects of Sost deficiency partially offset Opg deficiency-induced catabolism in cortical bone

Administration of an anti-sclerostin antibody enhances Wnt/β-catenin signaling, resulting in a significant increase in bone mass by stimulating bone formation and suppressing bone resorption. Wnt/β-catenin signaling upregulates the expression of osteoprotegerin (Opg), a key regulator that inhibits osteoclast differentiation and suppresses bone resorption. However, sclerostin-knockout (Sost-KO) mice exhibit increased bone formation without a corresponding suppression of bone resorption. Therefore, the role of Opg in Sost deficiency remains unclear.

To determine whether the osteogenic effects of Sost deficiency depend on the presence of Opg, we compared femoral bone mass among Sost/Opg double-knockout (DKO), Sost-KO, Opg-KO, and C57BL/6 (WT) mice.

High-resolution imaging and histological analysis revealed that cortical bone mass was significantly higher in DKO mice compared with WT and Opg-KO mice. In contrast, trabecular bone mass was reduced in DKO mice compared with WT mice, and the number of TRAP-positive osteoclasts and serum CTX levels, a bone resorption marker, were significantly higher in DKO mice compared with Sost-KO mice. To further examine the role of bone resorption in DKO mice, an anti-RANKL antibody was administered to these mice. This treatment markedly increased both trabecular and cortical bone mass. Bone resorption was almost completely suppressed in antibody-treated DKO mice compared with vehicle-treated mice, while bone formation markers, including the mineral apposition rate, were maintained at approximately one-third the levels of vehicle-treated mice.

These findings indicate that the enhanced bone formation in DKO mice primarily increases cortical bone mass without inhibiting bone resorption. The osteogenic effects of Sost deficiency are independent of Opg.