A critical role for interleukin-6 family-mediated Stat3 activation in osteoblast differentiation and bone formation

Interleukin-6 Directly Inhibits Osteoclast Differentiation by Suppressing Receptor Activator of NF-κB Signaling Pathways

“…7A) (7,18). Thus, predicting the net effects of IL-6 on bone homeostasis in vivo is difficult (8,15,(17)(18)(19)(20). Effects of IL-6 on bone formation in vivo are determined by the concentrations and combination of IL-6 family cytokines and soluble IL-6 receptor that are present in the areas around the sites of interaction between osteoblasts and osteoclast progenitors (7,18).…”

“…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).…”

“…To this end, we disrupted the STAT3 gene in an osteoblast-specific manner. The resulting osteoporotic phenotype clearly demonstrated that STAT3 signaling in osteoblasts in vivo has a positive regulatory role in the differentiation of this cell type, leading to bone formation but not osteoclastogenesis (8). On the other hand, other groups have reported that hematopoietic cell-specific STAT3-deficient mice also display an osteoporotic phenotype but due to the augmentation of osteoclast differentiation (17).…”

Stat3 Signaling Cascade in the Differentiation, Growth and Functions of Bone Cells

“…Universal Stat3 deficiency is lethal at embryonic day seven, a loss that cannot be compensated for by other Stat proteins. Itoh et al [22] bred a strain of mice that had a point mutation in the tyrosine at position 759 (gp130F759/F759). This specific tyrosine residue provides the binding site for cytokines that act as suppressors of the Jak-Stat3 pathway.…”

“…Since the suppressor of the gp130-mediated Stat3 signaling cascade was knocked out, the Jak-Stat3 pathway was enhanced. Conversely, Itoh et al [22] conditionally knocked down the Stat3 protein in osteoblasts using a type I collagen promoter. The control and experimental groups underwent bone histomorphometry of the vertebrae and tibias, bone mineral density scans, and osteoblast isolation.…”