Pathophysiology
Clinical meaning
Advanced understanding of osteoporosis requires knowledge of the molecular pathways governing bone cell differentiation and activity beyond the RANK/RANKL/OPG axis. The canonical Wnt/β-catenin signaling pathway is the master regulator of osteoblast differentiation and bone formation. Wnt ligands bind to the Frizzled receptor and its co-receptor LRP5/6 on mesenchymal stem cells, inhibiting the destruction complex (GSK-3β, axin, APC) and allowing β-catenin to accumulate in the cytoplasm and translocate to the nucleus where it activates transcription factors (TCF/LEF) that drive osteoblast commitment, proliferation, and survival. Simultaneously, Wnt signaling suppresses osteoclastogenesis by upregulating OPG expression in osteoblasts. Sclerostin, a glycoprotein encoded by the SOST gene and produced almost exclusively by osteocytes (the mechanosensory cells embedded within mineralized bone matrix), acts as a potent inhibitor of Wnt signaling by binding to LRP5/6 and preventing Wnt ligand engagement. When mechanical loading is applied to bone, osteocytes downregulate sclerostin production, releasing the brake on Wnt signaling and promoting bone formation at sites of mechanical strain. In disuse and aging, sclerostin levels rise, suppressing formation and contributing to net bone loss. Cathepsin K is a cysteine protease...