Induction of bone formation by activated monocytes / macrophages depends on Oncostatin M signaling

Bone resorption by osteoclasts and bone formation by osteoblasts are tightly coupled processes implicating factors in TNF, bone morphogenetic protein and Wnt families. In osteoimmunology, macrophages were described as another critical cell population regulating bone formation by osteoblasts but the coupling factors were not identified. Using a high throughput approach, we identified here Oncostatin M (OSM), a cytokine of the IL-6 family, as a major coupling factor produced by activated circulating CD14 + or bone marrow CD11b + monocytes/macrophages that induces osteoblast differentiation and matrix mineralization from human mesenchymal stem cells (MSC) while inhibiting adipogenesis. Upon toll-like receptors (TLRs) activation by lipopolysaccharide or endogenous ligands, OSM was produced in classically activated inflammatory M1 and not M2 macrophages, through a cyclooxygenase-2 and prostaglandin-E2 regulatory loop. Stimulation of osteogenesis by activated monocytes/macrophages was prevented using neutralizing antibodies or siRNA to OSM, OSM receptor subunits gp130 and OSMR or to the downstream transcription factor STAT3. The induced osteoblast differentiation program culminated with enhanced expression of C/EBPδ (CCAAT-enhancer-binding protein δ), Cbfa1 and alkaline phosphatase. Overexpression of OSM in the tibia of mice has led to new bone apposition with no sign of bone resorption. Two other cytokines had also a potent role in bone formation induced by monocytes/macrophages and TLRs activation: IL-6 and Leukemia inhibitory factor. We propose that during bone inflammation, infection or injury, the IL-6 family signaling network activated by macrophages and TLR ligands stimulates bone formation that is largely uncoupled from bone resorption and is thus an important target for anabolic bone therapies. 3 \body Bone is a dynamic mineralized tissue which is continuously resorbed by osteoclasts and rebuilt by osteoblasts. Osteoclast precursors are hematopoietic cells of the monocyte/macrophage lineage whereas osteoblast precursors are multipotent mesenchymal stem cells (MSC) that can also give rise to adipocytes and chondrocytes. Under physiological conditions, bone resorption is precisely replaced by new bone formation and therefore osteoclast and osteoblast activities are tightly coupled. Indeed, osteoblasts control osteoclast differentiation mainly through RANKL (receptor activator of nuclear factor kappa-B ligand) and inversely osteoclast control osteoblast differentiation through Wnt10b and BMP6 (bone morphogenetic protein 6) for example (1, 2). Immune cells such as T lymphocytes also control bone homeostasis or pathology in a field of research called osteoimmunology. More recently, bone resident macrophages, termed osteomacs, have been described as another critical immune cell population regulating bone formation by osteoblasts (3). However the coupling factors produced by osteomacs were …