Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation

Zhao, Ming; Harris, S. E.; Horn, Dominik; Geng, Zhaopo; Nishimura, Riko; Mundy, Gregory R.; Chen, Di

doi:10.1083/jcb.200109012

Cited by 160 publications

(163 citation statements)

References 55 publications

Supporting

Mentioning

153

Contrasting

Unclassified

Order By: Relevance

“…Another transcription factor, Atf4 regulates bone matrix deposition by mature osteoblasts [25]. Furthermore, several signaling pathways have been shown to regulate postnatal osteoblast function including Ihh [26], Wnt/Lrp5 [27], TGFb-BMP/Smads [28][29][30], BMP/MEKK2/MEK5-7/Jnk [31], b-adrenergic [32], IGF-1 [16], insulin [33] and PTH signaling [34]. The p38 MAPK pathway has been recently shown to be an essential regulator of osteoblastogenesis during skeletogenesis [12,13].…”

Section: Discussionmentioning

confidence: 99%

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

Thouverey

Caverzasio

2012

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Bone continuously remodels throughout life by coordinated actions of osteoclasts and osteoblasts. Abnormalities in either osteoclast or osteoblast functions lead to bone disorders. The p38 MAPK pathway has been shown to be essential in controlling osteoblast differentiation and skeletogenesis. Although p38a is the most abundant p38 member in osteoblasts, its specific individual contribution in regulating postnatal osteoblast activity and bone metabolism is unknown. To elucidate the specific role of p38a in regulating osteoblast function and bone homeostasis, we generated mice lacking p38a in differentiated osteoblasts. Osteoblast-specific p38a knockout mice were of normal weight and size. Despite non-significant bone alterations until 5 weeks of age, mutant mice demonstrated significant and progressive decrease in bone mineral density from that age. Adult mice deficient in p38a in osteoblasts displayed a striking reduction in cancellous bone volume at both axial and appendicular skeletal sites. At 6 months of age, trabecular bone volume was reduced by 62 % in those mice. Mutant mice also exhibited progressive decrease in cortical thickness of long bones. These abnormalities correlated with decreased endocortical and trabecular bone formation rate and reduced expressions of type 1 collagen, alkaline phosphatase, osteopontin and osteocalcin whereas bone resorption and osteoclasts remained unaffected. Finally, osteoblasts lacking p38a showed impaired marker gene expressions and defective mineralization in vitro. These findings indicate that p38a is an essential positive regulator of osteoblast function and postnatal bone formation in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

Thouverey

Caverzasio

2012

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…We next determined the function of dnALKs in BMP9 signaling pathway using the BMPR Smad-responsive reporter (40). Experimentally, C3H10T1/2 cells were transfected with 12xSBE-Luc reporter and infected with Ad-dnALKs or Ad-RFP for 24 h, and then stimulated with BMP9-CM.…”

Section: Endogenous Expression Of the Seven Type I Receptors In Mscs Andmentioning

confidence: 99%

TGFβ/BMP Type I Receptors ALK1 and ALK2 Are Essential for BMP9-induced Osteogenic Signaling in Mesenchymal Stem Cells

Luo

Tang

Huang

et al. 2010

Journal of Biological Chemistry

170

211

View full text Add to dashboard Cite

Mesenchymal stem cells (MSCs) are bone marrow stromal cells that can differentiate into multiple lineages. We previously demonstrated that BMP9 is one of the most potent BMPs to induce osteogenic differentiation of MSCs. BMP9 is one of the least studied BMPs. Whereas ALK1, ALK5, and/or endoglin have recently been reported as potential BMP9 type I receptors in endothelial cells, little is known about type I receptor involvement in BMP9-induced osteogenic differentiation in MSCs. Here, we conduct a comprehensive analysis of the functional role of seven type I receptors in BMP9-induced osteogenic signaling in MSCs. We have found that most of the seven type I receptors are expressed in MSCs. However, using dominant-negative mutants for the seven type I receptors, we demonstrate that only ALK1 and ALK2 mutants effectively inhibit BMP9-induced osteogenic differentiation in vitro and ectopic ossification in MSC implantation assays. Protein fragment complementation assays demonstrate that ALK1 and ALK2 directly interact with BMP9. Likewise, RNAi silencing of ALK1 and ALK2 expression inhibits BMP9-induced BMPR-Smad activity and osteogenic differentiation in MSCs both in vitro and in vivo. Therefore, our results strongly suggest that ALK1 and ALK2 may play an important role in mediating BMP9-induced osteogenic differentiation. These findings should further aid us in understanding the molecular mechanism through which BMP9 regulates osteogenic differentiation of MSCs. Mesenchymal stem cells (MSCs),2 representing a very small fraction of the total population of nucleated cells in bone marrow are adherent marrow stromal cells that can self-renew and differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages (1-4). Bone morphogenetic proteins (BMPs), members of the TGF␤ superfamily, play an important role in stem cell biology (5, 6) and function to regulate cell proliferation and differentiation during development (7, 8). Several BMPs have been shown to regulate osteoblast differentiation and subsequent bone formation (3, 4, 7-9) and genetic disruptions of these factors have resulted in various skeletal and extraskeletal abnormalities during development (9, 10). We have conducted a comprehensive analysis of the osteogenic activity of 14 human BMPs and demonstrated that BMP9 is one of the most potent BMPs in promoting osteogenic differentiation of MSCs (3,11,12). We also demonstrated that osteogenic BMP9 regulates a distinct set of downstream targets in MSCs (13-16).BMP9 (a.k.a., GDF2) was originally identified from fetal mouse liver cDNA libraries, and is a relatively uncharacterized member of the BMP family (17). BMP9 is highly expressed in the developing mouse liver, and recombinant human BMP9 stimulates hepatocyte proliferation (17,18). It has been reported that BMP9 may play role in regulating glucose and iron homeostasis in liver (19,20). BMP9 has been shown to be a potent synergistic factor for hematopoietic progenitor generation and colony formation (21) and may play a role in the induction and main...

show abstract

“…A mouse osteoblast cell line (2T3 cells) was monitored using a mineralized matrix formation assay as described by Bhargava et al and cultured as described previously [7,14,105]. Mineralization of the murine osteoblastic 2T3 cell line has been extensively studied using physical techniques, electron microscopy and histological techniques.…”

Section: Mineralized Bone Matrix Formation Assaymentioning

confidence: 99%

“…Mineralization of the murine osteoblastic 2T3 cell line has been extensively studied using physical techniques, electron microscopy and histological techniques. This cell line (2T3) undergoes exogenous BMP2-induced mineralized matrix indistinguishable from normal bone-mineral hydroxyapatite in vitro [7,14,105]. The cells were plated in 24-well culture plates at a density of 2 × 10 4 cells/well and cultured with minimal essential medium (MEM) supplemented with 10% FCS.…”

Section: Mineralized Bone Matrix Formation Assaymentioning

confidence: 99%

MEPE has the properties of an osteoblastic phosphatonin and minhibin

Rowe

Kumagai²,

Gutiérrez³

et al. 2004

Bone

247

277

View full text Add to dashboard Cite

Matrix extracellular phosphoglycoprotein (MEPE) is expressed exclusively in osteoblasts, osteocytes and odontoblasts with markedly elevated expression found in X-linked hypophosphatemic rickets (Hyp) osteoblasts and in oncogenic hypophosphatemic osteomalacia (OHO) tumors. Because these syndromes are associated with abnormalities in mineralization and renal phosphate excretion, we examined the effects of insect-expressed full-length human-MEPE (Hu-MEPE) on serum and urinary phosphate in vivo, 33 PO 4 uptake in renal proximal tubule cultures and mineralization of osteoblast cultures. Dose-dependent hypophosphatemia and hyperphosphaturia occurred in mice following intraperitoneal (IP) administration of Hu-MEPE (up to 400 μg kg -1 31 h -1 ), similar to mice given the phosphaturic hormone PTH (80 μg kg -1 31 h -1 ). Also the fractional excretion of phosphate (FEP) was stimulated by MEPE [65.0% (P < 0.001)] and PTH groups [53.3% (P < 0.001)] relative to the vehicle group [28.7% (SEM 3.97)]. In addition, Hu-MEPE significantly inhibited 33 PO 4 uptake in primary human proximal tubule renal cells (RPTEC) and a human renal cell line (Hu-CL8) in vitro (V max 53.4% inhibition; K m 27.4 ng/ ml, and V max 9.1% inhibition; K m 23.8 ng/ml, respectively). Moreover, Hu-MEPE dose dependently (50-800 ng/ml) inhibited BMP2-mediated mineralization of a murine osteoblast cell line (2T3) in vitro. Inhibition of mineralization was localized to a small (2 kDa) cathepsin B released carboxy-terminal MEPE peptide (protease-resistant) containing the acidic serineaspartate-rich motif (ASARM peptide). We conclude that MEPE promotes renal phosphate excretion and modulates mineralization.

show abstract

Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation

Cited by 160 publications

References 55 publications

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition

TGFβ/BMP Type I Receptors ALK1 and ALK2 Are Essential for BMP9-induced Osteogenic Signaling in Mesenchymal Stem Cells

MEPE has the properties of an osteoblastic phosphatonin and minhibin

Contact Info

Product

Resources

About