Interleukin-6 (IL-6) is a multifunctional cytokine produced by various cells to regulate hematopoiesis, inflammation, immune responses, and bone homeostasis. IL-6 is also known to modulate the differentiation of osteoblasts and osteoclasts. IL-6 is believed to play a positive regulatory role in osteoclast differentiation by inducing the expression of receptor activator of NF-B ligand (RANKL) on the surface of osteoblasts: RANKL then interacts with RANK expressed on osteoclast progenitors, inducing osteoclast differentiation via the RANK signaling pathway, which involves NF-B, JNK, and p38. In this report, we demonstrate that IL-6 can also directly act on osteoclast progenitors to suppress their differentiation via an inhibition of RANK signaling pathways. IL-6 specifically suppressed RANK-mediated IB degradation and JNK activation. Microarray analysis revealed that costimulation with IL-6 and RANKL up-regulates the transcription of MKP1 and MKP7, which encode enzymes that dephosphorylate JNK, and down-regulates the transcription of Senp2 and Cul4A, which are related to the ubiquitin pathway. Thus, IL-6 directly acts on osteoclast progenitors and suppresses their differentiation by regulating the transcription of specific genes related to MAPK phosphatases and the ubiquitin pathway.Bone tissue is continuously remodeled under physiological conditions (1), but dysregulation of the balance between bone formation and resorption induces pathological conditions, including osteoporosis and osteosclerosis. Bone remodeling is maintained by two key cell populations, osteoblasts and osteoclasts, which are regulated by cytokines, hormones, and growth factors (2, 3). Among the cytokines, the interleukin-6 (IL-6) 3 family cytokines are known to modulate both osteoblast and osteoclast differentiation (3-5).IL-6 is a multifunctional cytokine produced by various cell types that regulates hematopoiesis, acute phase reactions, immune responses, and bone homeostasis (6 -8). The receptor for IL-6 consists of a ligand-binding subunit and a common signal-transducing subunit, gp130 (9). gp130 contains a number of tyrosine residues in its cytoplasmic region, as well as four copies of the YXXQ motif, which is required for the tyrosine phosphorylation of STAT3. Activated STAT3 dimerizes, enters the nucleus, and regulates the transcription of various genes that regulate cell survival, proliferation, and differentiation in a cell-specific manner (6, 8). Tyr-759 of gp130 is required for the tyrosine phosphorylation of Src homology 2 domain-containing tyrosine phosphatase (SHP)-2, which activates the MAPK ERK via a complex comprising SHP2, Gab1/2, and phosphatidylinositol 3-kinase p85 (10 -12).It has been reported that IL-6 together with soluble IL-6 receptor acts to induce the expression of receptor activator of NF-B ligand (RANKL) on the surface of osteoblasts. RANKL interacts with RANK, which is expressed on the surface of osteoclast progenitors. Coculture experiments have demonstrated that this interaction is indispensable for the differen...

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Grb2-associated binder 2 (Gab2) is an adaptor molecule that can be tyrosine phosphorylated by various growth factors and cytokines. Gab2 is known to play a role in signaling pathways downstream of cytokines that regulate bone homeostasis, including M-CSF, RANKL, and IL-6. To clarify the role of Gab2 in bone homeostasis during distinct phases of skeletal development, we compared phenotypic changes in bone homeostasis in Gab2(-/-) mice at two different ages. Although Gab2(-/-) mice showed increased bone volume at both time points, the reasons underlying the increased bone volume differed. At 6 weeks, the increased bone volume was due to enhanced bone resorption and bone formation, indicating that Gab2 plays a negative regulatory role for both osteoclastogenesis and osteoblast differentiation. At 12 weeks, the increased bone volume resulted from reduced osteoclast differentiation, indicating that Gab2 plays a positive regulatory role for osteoclastogenesis. Thus, Gab2 plays opposite roles in osteoclastogenesis during the phases of skeletal development and maintenance.