P38 and ERK1/2 MAPKs Act in Opposition to Regulate BMP9-Induced Osteogenic Differentiation of Mesenchymal Progenitor Cells

Abstract

Although previous studies have demonstrated that BMP9 is highly capable of inducing osteogenic differentiation and bone formation, the precise molecular mechanism involved remains to be fully elucidated. In this current study, we explore the possible involvement and detail effects of p38 and ERK1/2 MAPKs on BMP9-indcued osteogenic differentiation of mesenchymal progenitor cell (MPCs). We find that BMP9 simultaneously stimulates the activation of p38 and ERK1/2 in MPCs. BMP9-induced early osteogenic marker, such as alkaline phosphatase (ALP), and late osteogenic markers, such as matrix mineralization and osteocalcin (OC) are inhibited by p38 inhibitor SB203580, whereas enhanced by ERK1/2 inhibitor PD98059. BMP9-induced activation of Runx2 and Smads signaling are reduced by SB203580, and yet increased by PD98059 in MPCs. The in vitro effects of inhibitors are reproduced with adenoviruses expressing siRNA targeted p38 and ERK1/2, respectively. Using mouse calvarial organ culture and subcutaneous MPCs implantation, we find that inhibition of p38 activity leads to significant decrease in BMP9-induced osteogenic differentiation and bone formation, however, blockage of ERK1/2 results in effective increase in BMP9-indcued osteogenic differentiation in vivo. Together, our results reveal that p38 and ERK1/2 MAPKs are activated in BMP9-induced osteogenic differentiation of MPCs. What is most noteworthy, however, is that p38 and ERK1/2 act in opposition to regulate BMP9-induced osteogenic differentiation of MPCs.

Osteoblastic differentiation of stromal ST-2 cells from octacalcium phosphate exposure via p38 signaling pathway

“…Previous studies reported that BMP-2 is involved in activating p38 in ST-2 cells accompanied by osteoblastic differentiation with increasing ALP activity and osteocalcin mRNA 25) . Another study showed that the enhanced ALP activity by BMP-9 is inhibited with SB203580 in a dose-dependent manner in murine mesenchymal progenitor in C3H10 1/2 cells 26) . The signaling pathway stimulated by OCP in the present study, most likely caused by calcium diffusion into the crystals and Pi release from the crystals during the dissolution and conversion of OCP into HA, may follow a similar mechanism as BMPs.…”

“…The mitogen-activated protein kinase (MAPK)/extracellular related kinase (ERK) signaling pathway is involved in activating the early stage of the differentiation of bone marrow-derived mesenchymal stem cells into osteoblasts 22,23) . Signal transduction of p38 is another important pathway in osteoblast differentiation and stimulated by the bone morphogenetic protein (BMP) family [24][25][26][27] . Calcium phosphate ceramics, such as calciumdeficient HA and β-tricalcium phosphate (β-TCP), have been shown to induce osteoblast differentiation in human bone marrow stromal cells 27) .…”

Nitric Oxide Activates Signaling by c-Raf, MEK, p-JNK, p38 MAPK and p53 in Human Mesenchymal Stromal Cells inhibits their Osteogenic Differentiation by Blocking Expression of Runx2

“…We provide evidence that the elevated production of NO blocks the osteogenic differentiation of MSC by reducing the expression of Runx2 [54,71]. Blocking osteogenesis of MSC may allusively contribute to the formation of the characteristic interface membrane, which contains activated fibroblasts that resorb the bone matrix [72].…”

“…Moreover, elevated NO contributes to loss of bone mass and therefore seems to promote osteoporosis [73][74][75]. However, the regulation of Runx2 is complex and both activatory and inhibitory effects were observed, depending on the experimental set-up [71,76] (Figure 5). In contrast, low doses of NO may facilitate osteogenic differentiation or NO facilitated MSC-mediated tissue repair in vivo [77,78].…”

“…BMPs, GFs and the ECM regulate the gene expression required for osteogenic differentiation, proliferation and survival or apoptosis of MSC (thin solid arrows). Depending on the cell, MEK1/2 block the activation and nuclear translocation of SMADs (thick line with rombus), thus inhibiting expression of Runx2 (71). Nitric oxide radicals cause a transiently elevated phosphorylation of MEK1/2, p38MAPK, JNK, and p53 (thin dashed arrows) involved in proliferation, survival and apoptosis.…”