p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner

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.

Endothelial Progenitor Cells Induce Osteogenic Differentiation in Co-cultured Mesenchymal Stem Cells via the MAPK Signaling Pathway

“…Reports have also indicated that the p38MAPK-dependent signaling pathway enhances Col-I synthesis and bone mineralization in rats [48]. p38MAPK signaling pathway is involved in osteoblast proliferation and differentiation, and plays important roles during osteogenic differentiation [49,50]. Based on these studies, we speculate EPCs induce osteogenic differentiation in co-cultured mesenchymal stem cells via the p38MAPK signaling pathway.…”

Activating; ‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK

“…Indeed, a previous study showed that both p38a and p38b knock-out mice exhibited lower bone mass compared with wild-type mice, although this phenotype was mainly affected by osteoblast activity (33). Intriguingly, p38a conditional knockout mice in OCs exhibited distinct alterations in bone resorption at 2.5 and 6 mo of age, and p38a can positively or negatively regulate osteoclastogenesis in different cultural conditions in vitro (34). In reality, there are limited studies showing the role of p38 in the selective inhibition on osteoclastogenesis (35,36).…”

Caffeic Acid Inhibits RANKL and TNF-α-induced Phosphorylation of p38 Mitogen-activated Protein Kinase in RAW-D Cells

“…p38 MAPK is a member of MAPK family that has an important role in tissue development and homeostasis functions such as cell differentiation, apoptosis, maturation, and cytokine production which initiates osteoclastogenesis. (8,9) After being activated, p38 MAPK will induce important transcription factors such as NFkB and NFATc1. (8,9,12) Inhibition of p38 MAPK was reported to fully diminish RANKL and TNF-α-induced osteoclast formation.…”

“…(8,9) After being activated, p38 MAPK will induce important transcription factors such as NFkB and NFATc1. (8,9,12) Inhibition of p38 MAPK was reported to fully diminish RANKL and TNF-α-induced osteoclast formation. (15) In the present study, RANKL and TNF-α induced formation of TRAP + PNCs, meanwhile pretreatment of caffeic acid could diminish the formation of RANKL and TNF-α-induced TRAP + PNCs.…”

“…(6,7) Among the MAPK family, p38 MAPK has been reported to play an important role in osteoclastogenesis. (8,9) Caffeic acid attracts much special attention because of its ability to protect the human from several diseases, including cancer (10,11) and bone resorption (12)(13)(14). Caffeic acid induced osteosarcoma cells into apoptosis by activation of Caspases, including Caspase-8, -9 and -3.…”