Cumulative evidence has shown that osteocytes and hypertrophic chondrocytes, rather than osteoblastic cells, serve as major suppliers of RANKL during the remodeling process.28,43 Since osteocytes are a critical component in identification of the skeletal load,44 abnormal mechanical force activates RANKL signaling and osteoclastogenesis, leading to aberrant bone remodeling and osteosclerosis. The gene discussed is TNFSF11; the disease is osteosclerosis.