Synthetic organochlorines exert bone anabolic activity by modulating CCN3 signaling in osteoblasts

Humans exposed to synthetic organochlorine pesticides such as DDT (p,p'-dichlorodiphenyltrichloroethane) have a higher risk of developing diabetes and other metabolic disorders. This investigation, however, uncovered a surprisingly beneficial effect of these compounds on bone metabolism. In elderly Chinese subjects, bone mineral density (BMD) correlated positively with serum p,p'dichlorodiphenyldichloroethylene (DDE) levels, independent of diabetic status. Mice exposed to DDE orally exhibited increased bone mass, accelerated regeneration of bone defects, and reduced bone loss following ovariectomy. In cultured osteoblasts, DDE treatment promoted matrix mineralization, accompanied by altered gene profiles implicating downstream targets of the cellular communication network factor 3 (CCN3) signaling pathway. Additional studies demonstrated that DDE upregulated CCN3 signaling in osteoblasts by relieving FOXO1 inhibition. Taken together, our findings identify a previously unrecognized role of organochlorine derivatives in bone formation by modulating FOXO1-CCN3 signaling.