The Role of IGF‐I Signaling in Regulating Osteoclastogenesis

The proximal tibiae from IGF‐I knockout mice (KO) show increased trabecular number and connectivity despite decreased bone formation, suggesting a concomitant reduction in bone resorption. Therefore, we examined the role of IGF‐I on osteoclastogenesis. The number of tartrate‐resistant acid phosphatase (TRAP) osteoclasts (N.OCL) in the KO mice were 76% of that observed in the wild‐type (WT) mice in the proximal tibia. In vitro, the administration of RANKL and M‐CSF to osteoclast (OCL) precursors (spleen cells) from WT mice stimulated the formation of multinucleated TRAP positive OCL. OCL precursors from the KO mice formed only mononuclear or binuclear TRAP positive OCL and in lesser numbers (55% of WT). IGF‐I (10 ng/ml) further increased OCL number, number of nuclei and function in the WT cultures, but was much less effective in the cultures from KO mice. When KO osteoblasts (KOOB) and WT OCL precursors (spleen cells, WTSP) were co‐cultured (KOOB:WTSP), the N.OCL formed was only 11% of that from co‐cultures of WTOB and WTSP (WTOB:WTSP), consistent with the reduced expression of RANK and RANKL in bone from KO mice. Pre‐treatment of KOOB by IGF‐I 10 ng/ml for 9 days partially rescued OCL formation in KOOB and WTSP co‐cultures (58% of WTOB:WTSP). In summary, our results indicate that IGF‐I stimulates OCL multinucleation and increases their function. IGF‐I is required for the normal interaction between the OB and OCL via its regulation of RANKL and RANK expression. The role of OBs in stimulating osteoclastogenesis is more impacted by lack of IGF‐I than the ability of OCL precursors to respond to osteoblastic stimulation, although both OBs and OCL precursors appear to function subnormally in the absence of IGF‐I.