Role Of P38? MAPK In Bone Development And Bone Metabolism

Bone remodeling is carried out by mesenchymal stem cell-derived osteoblasts and monocyte-derived osteoclasts and coupling between bone formation and resorption is critical in maintaining proper bone mass/density.Bone marrow mesenchymal stem cells(MSCs)are capable of self-renewal and differentiating into osteoblasts,chondrocytes,and adipocytes.Monocytes derived from the hematopoietic stem cells can differentiate into osteoclasts,which requires transcription factors such as PU.1,Mitf,c-Fos,and NFATc1.How differentiation of osteoclasts and osteoblasts from their respective progenitors is regulated and the coupling mechanisms remain not fully understood.We show that ablation of p38? in Prx1+ MSCs exhibited osteoporotic phenotypes,growth plate defects,and increased bone marrow fat,secondary to biased MSC differentiation from osteoblast/chondrocyte to adipocyte.The defect in MSC ostogenic commitment is attributable to hyperactivation of Tak1-NF-?B signaling.Ablation of p38? in Dermo1+ MSCs,another mesenchymal marker,displayed only osteoporptic phenotypes.In addition,Prx1-Cre;p38?f/f mice show increased osteoclastogenesis and bone resorption,which is secondary to decreasd expression of OPG by the MSCs.p38? activates downstream transcription factor Creb to regulate the expression of OPG.We found that estrogen also activates p38? to maintain OPG expression in MSCs,and Prx1-Cre;p38?f/f mice are not responsive to estrogen deficienty-induced bone loss.Then we ablated p38? in Lys M+ monocytes and investigated the potential roles of p38? MAPK in osteoclastogenesis and bone resorption.p38? deficiency promoted monocyte proliferation but regulated monocyte differentiation into osteoclast in a cell density dependent manner.The Lys M-Cre;p38?f/f mice showed a minor increase in bone mass at 2.5 month of age,associated with a modest decrease in bone resorption,but developed osteoporosis at 6 month of age,coupled with an increase in bone resorption.p38? ablation led to an greater increase in the pool of monocytes in 6-month-old mice than 2.5-month-old mice.Thus,the balance of monocyte proliferation and differentiation leads to opposite bone resorption alteration in 2.5-and 6-month-old mice.Moreover,monocyte-specific p38? ablation resulted in a decrease in bone formation,MSC proliferation,and osteogenic differentiation,accompanied by decreased expression of PDGF-AA and BMP2.The expression of PDGF-AA and BMP2 was positively regulated by transcription factor Creb,which has binding sites in the promoters of PDGF-AA and BMP2.These data uncover the molecular mechanisms by which p38? MAPK regulates MSCs differentiation into osteoblasts and monocytes differentiation into osteoclasts,and coupling between MSCs and monocytes in skeletal development and bone remodeling.