The ratio of messenger RNA levels of receptor activator of nuclear factor kappa B ligand to osteoprotegerin correlates with bone remodeling indices in normal human cancellous bone but not in osteoarthritis

skeletal disease. Bone remodeling is initiated by osteoclastic resorption f ollowed by osteoblastic formation of new bone. Receptor activator of nuclea r factor KB ligand (RANKL) is a newly described regulator of osteoclast for mation and function, the activity of which appears to be a balance between interaction with its receptor RANK and with an antagonist binding protein o steoprotegerin (OPG). Therefore, we have examined the relationship between the expression of RANKL, RANK, and OPG and indices of bone structure and tu rnover in human cancellous bone from the proximal femur. Bone samples were obtained from individuals with osteoarthritis (OA) at joint replacement sur gery and from autopsy controls. Histomorphometric analysis of these samples showed that eroded surface (ES/BS) and osteoid surface (OS/BS) were positi vely associated in both control (p < 0.001) and OA (p < 0.02), indicating t hat the processes of bone resorption and bone formation remain coupled in O A, as they are in controls. RANKL, OPG, and RANK messenger RNA, (mRNA) were abundant in human cancellous bone, with significant differences between co ntrol and OA individuals. In coplotting the molecular and histomorphometric data, strong associations were found between the ratio of RANKL/OPG mRNA a nd the indices of bone turnover (RANKL/OPG vs. ES/BS: r = 0.93, p < 0.001; RANKL/OPG vs. OS/BS: r = 0.80, p < 0.001). These relationships were not evi dent in trabecular bone from severe OA, suggesting that bone turnover may b e regulated differently in this disease. We propose that the effective conc entration of RANKL is related causally to bone turnover.