Abstract
Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α−/− cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.
Highlights
Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts
Osteoblasts are derived from mesenchymal stem/stromal cells (MSCs), which are defined by lineage-specific transcription factors Runx[2] and Osterix[5,6,7], while osteoclasts are derived from the hematopoietic stem cell-monocyte lineage, which requires transcription factors such as PU.[1], NF-κB, c-Fos, and NFATc18
P38 MAPKs can be activated by estrogen in MSCs, which controls the expression of OPG to regulate osteoclastogenesis and bone resorption[23]
Summary
P38 MAPKs can be activated by growth factors and cytokines, some of which, e.g., BMPs, TGFβ, and RANKL, play important roles in bone development and remodeling. We ablated p38αin LysM-labeled monocytes and found that p38αinhibits monocyte proliferation and regulates osteoclastic differentiation in a cell density/proliferation-dependent manner It controls the expression of PDGF-AA and BMP2 in osteoclasts to affect osteoblastogenesis and bone formation. We found that p38 MAPKs are highly activated in monocytes of older mice compared to young mice, suggesting that p38αmay display a stronger effect on osteoclastogenesis in old mice than in young mice and as such, p38 ablation may show more robust effects on monocyte proliferation and differentiation This may be a reason why p38αdeficient mice showed a great decrease in bone mass and developed osteoporosis at 6 month of age, attributable to an increase in osteoclastogenesis and bone resorption. P38αmay mediate the effects of RANKL, BMPs, and other cytokines, on bone remodeling, and represent a drug target for osteoporosis therapy
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