The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice

Abstract

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-β-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38β agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

“…(46) Phosphorylation of Ser17, 261, and 298 by p38 MAP kinase promotes the association of Runx2 with its coactivator, CREB-binding protein (CBP). (47) In addition, Ser22 phosphorylated by PKCd and Thr341 phosphorylated by PKA are required for, respectively, FGF2 and PTH-induced Runx2 activation and osteoblastic differentiation. (48,49) Contrarily, the phosphorylation of Ser369, 373, and 377 by GSK3b was shown to inhibit Runx2 transcriptional activity.…”

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

“…Moreover, several reports have also indicated that the p38 pathway regulates the expression and activation of critical transcription factors implicated in osteoblastogenesis, i.e., Dlx5, Runx2, and Osx [5,[10][11][12].…”

“…More recently, an in vivo investigation has highlighted the physiological role of TGF-b-activated kinase 1 (TAK1) in osteoblastogenesis and bone formation [12]. TAK1 is a MAP3 K acting downstream of BMP and TGF-b receptors.…”

“…TAK1 is a MAP3 K acting downstream of BMP and TGF-b receptors. Although TAK1 can activate different signaling cascades, the MKK3/6-p38 pathway has been suggested as the main mediator of TAK1 function in osteoblasts [12]. Interestingly, p38b knockout mice have been shown to exhibit a low bone mass phenotype suggesting that loss of p38b is not compensated by p38a and therefore, that p38a and p38b may have different functions in bone formation and development [12].…”

“…Although TAK1 can activate different signaling cascades, the MKK3/6-p38 pathway has been suggested as the main mediator of TAK1 function in osteoblasts [12]. Interestingly, p38b knockout mice have been shown to exhibit a low bone mass phenotype suggesting that loss of p38b is not compensated by p38a and therefore, that p38a and p38b may have different functions in bone formation and development [12]. This hypothesis has been confirmed by in vitro analyses demonstrating that p38a regulates early osteoblast differentiation whereas p38b controls late osteoblast maturation [12].…”