A fragment of the hypophosphatemic factor, MEPE, requires inducible cyclooxygenase‐2 to exert potent anabolic effects on normal human marrow osteoblast precursors

Nagel, David; Khosla, Sundeep; Sanyal, Abhik Kumar; Rosen, David; Kumagai, Yoshinari; Riggs, B. Lawrence

doi:10.1002/jcb.20249

Cited by 20 publications

(26 citation statements)

References 30 publications

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“…MEPE was first identified in tumor conditioned medium and osteosarcoma cell lines. Multiple experimental observations support that MEPE is correlated positively to serum P i and has an important role in negative regulation of mineralization in the skeleton (26,27).…”

Section: Clustering Analysis Indicates Pth-(1-34)-treated Samples Havmentioning

confidence: 92%

Determination of Dual Effects of Parathyroid Hormone on Skeletal Gene Expression in Vivo by Microarray and Network Analysis

Li¹,

Líu²,

Qin³

et al. 2007

Journal of Biological Chemistry

165

148

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Parathyroid hormone (PTH) stimulates bone formation when injected daily but causes severe bone loss with continuous infusion. The mechanism of its paradoxical effects is still elusive. In this study, we compared changes in the gene expression profile in bone induced by intermittent or continuous treatment with three different PTH peptides, PTH-(1-34), -(1-31), and -(3-34), in Sprague-Dawley female rats. PTH-(1-34) regulated numerous genes (ϳ1,000), but differentially, in both regimes. PTH-(1-31) regulated a similar number of genes in the intermittent regimen but fewer in the continuous regimen, consistent with its less potent catabolic effect. PTH-(3-34) regulated very few genes in both regimes, which suggests the protein kinase C pathway plays a limited role in mediating the dual effects of PTH, whereas the cAMPdependent protein kinase A pathway appears to predominate. In the intermittent treatment, many genes encoding signaling mediators, transcription factors, cytokines, and proteases/ protease inhibitors are regulated rapidly and cyclically with each PTH injection; genes associated with skeletal development show a slowly accruing pattern of expression. With continuous treatment, some genes are regulated from 6 h, and the mRNA levels are sustained with a longer infusion, whereas others show a kinetic decrease and then increase later. Significant up-regulation of genes stimulating osteoclastogenesis in the anabolic regime suggests a provocative and paradoxical theme for the anabolic effect of PTH that a full anabolic response requires a transient up-regulation of genes classically associated with a resorptive response. Ingenuity pathway analysis was performed on the microarray data. A novel signaling network was established that is differentially regulated in the two PTH treatment regimes. Key regulators are suggested to be AREG, CCL2, WNT4, and cAMP-responsive element modulator. PTH,2 administered intermittently, stimulates bone formation in contrast to antiresorptive agents, which reduce bone resorption. Concerns with the limited improvement of antiresorptive treatments in severe osteoporosis led to a search for alternative anabolic agents (1). Teraparatide, recombinant human parathyroid hormone consisting of the first 34 of the 84 amino acids of human parathyroid hormone, has been shown to reduce significantly the risk of both vertebral and nonvertebral fractures in postmenopausal women and to significantly increase bone mineral density (2). It has become the only anabolic agent currently approved for the treatment of osteoporosis in the United States.Bone is a highly specialized form of connective tissue and dynamic organ in all higher vertebrates; it undergoes continuous regeneration. Bone remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion, with coupling of osteoclastic resorption and osteoblastic formation (3). This physiological process is coordinated and tightly regulated by local and endocrine factors to ensure that there is a balance between bone formation and ...

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Section: Clustering Analysis Indicates Pth-(1-34)-treated Samples Havmentioning

confidence: 92%

Determination of Dual Effects of Parathyroid Hormone on Skeletal Gene Expression in Vivo by Microarray and Network Analysis

Li¹,

Líu²,

Qin³

et al. 2007

Journal of Biological Chemistry

165

148

View full text Add to dashboard Cite

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“…In contrast, MEPE has been shown to have an anabolic effect on osteoblast differentiation. It is reported that AC-100 enhances osteogenesis by promoting osteoblast proliferation and differentiation like BMP-2 (8,9). Dentonin, which is the same as AC-100, promotes dental pulp stem cell proliferation in response to the dentin repair response (34,35).…”

Section: Mepe Expression Is Strongly Stimulated By Bmp-2 Treatment Anmentioning

confidence: 99%

“…Two functional domains of MEPE have been well defined; one is the centrally located motif that includes an RGD, cell adhesion domain, and a SGDG, glycosaminoglycan (GAG) interaction domain. AC-100, a 23-amino acid synthetic peptide comprised of RGD and SGDG, has demonstrated strong osteogenic activity (8,9). The other domain is a C-terminal ASARM motif that is common among the SIB-LING family proteins although they are not functionally conserved (10).…”

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confidence: 99%

Molecular Regulation of Matrix Extracellular Phosphoglycoprotein Expression by Bone Morphogenetic Protein-2

Cho¹,

Yoon²,

Woo³

et al. 2009

Journal of Biological Chemistry

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Matrix extracellular phosphoglycoprotein (MEPE) is mainly expressed in mineralizing tissues, and its C-terminal proteolytic cleavage product is an acidic-serine-asparate-rich-MEPE-associated motif (ASARM) that is a strong regulator of body phosphate metabolism and mineralization. There is sufficient data supporting a role for MEPE protein function in mineralization, however, little is known about the regulation of MEPE gene expression. As bone morphogenetic protein-2 (BMP-2) is one of the most important signals for calvarial mineralization and MEPE expression is higher in mineralized tissues, we attempted to uncover a regulatory circuit between BMP-2 and MEPE expression. Mepe expression is very low in proliferating MC3T3-E1 cells, but is dramatically increased in the mineralization stage and is strongly stimulated by treatment with BMP-2, even in proliferating cells. Overexpression and knockdown experiments of Smads, Dlx5, and Runx2 indicated that they are indispensable mediators of BMP-2-induced Mepe expression. In contrast, Msx2 showed strong inhibition of Mepe transcription. PHEX is an enzyme that prevents the release of the ASARM motif, a mineralization inhibitor, from the MEPE molecule. Thus, the MEPE/PHEX ratio may be a good indicator of mineralization progression because we found that the mRNA ratio and protein levels were low when osteoblasts were actively differentiating to the mineralization stage and the ratio was high when the cells reached the mineralization stage when it is assumed that osteocytes may protect themselves and make a space to survive from the mineralized matrix by releasing the ASARM motif. Collectively, MEPE expression is bone cell-specific and induced by the BMP-2 signaling pathway. In addition, the MEPE/PHEX ratio of the cell could be a very important barometer indicating the progression of tissue mineralization.Mineral homeostasis in the body is critical for healthy bones and teeth, and is generally regulated by the calcium-phosphate balance in the bone and kidney networks. In the past, the vitamin D/parathyroid hormone axis was assumed to be a single major circuit in bone-renal phosphate regulation, but recently, new bone-renal phosphate regulating factors have been identified. The finding of fibroblast growth factor 23 (FGF23), 2 phosphate-regulating genes with homologies to endopeptidases on the X chromosome (PHEX) and matrix extracellular phosphoglycoprotein (MEPE) genes, and their pathophysiological roles in the genetic diseases of mineral metabolism, have provided a great deal of insight into the understanding of bone-and mineral-related diseases. Among these, autosomal-dominant hypophosphatemic rickets (OMIM number 193100) is characterized by renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D 3 levels (1). Autosomal-dominant hypophosphatemic rickets is caused by a missense mutation of FGF23, which is resistant to proteolysis by PHEX and increases the half-life of full-length phosphaturic FGF23 (2). Second, X-linked hypophosphatemic...

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“…Mature osteoblast function is less influenced by the addition of truncated MEPE or AC-100. Evidence suggests that MEPE may be mediating some of its effects through the production of prostaglandins 29 and since COX-2 protein levels have been shown to correlate with integrin activation, 30 MEPE activation of FAK could likely shift the balance of cell:ECM interactions that result in COX-2 regulation. Furthermore, evidence suggests that PGE2 primarily acts in the first few days of in vitro models of osteogenesis to increase the numbers of cells likely to become mature osteoblasts.…”

Section: Discussionmentioning

confidence: 98%

“…Evidence suggests that AC-100 functions through the activation of integrins and that subsequent regulation of prostaglandin signaling through control of COX-2 is responsible for its ability to regulate osteoblast differentiation. 11 These observations have led to the possibility that AC-100 may have potential for use in the treatment of bone diseases associated with decreased bone formation and as part of surgical therapies.…”

mentioning

confidence: 98%

ASARM‐truncated MEPE and AC‐100 enhance osteogenesis by promoting osteoprogenitor adhesion

Sprowson

McCaskie

Birch

2008

Journal Orthopaedic Research

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Matrix extracellular phosphoglycoprotein (MEPE) is a member of the SIBLING (Small Integrin-Binding Ligand, N-linked Glycoprotein) family of secreted glycophosphoproteins. Several previous studies have demonstrated that MEPE and its peptide motif, AC-100, may regulate bone mass and influence osteoblast activity, suggesting its potential for inclusion in novel therapeutic strategies aimed at increasing osteogenesis. Our study uses in vitro approaches to assess how adhesion of nonadherent cells is influenced by MEPE and whether response to MEPE is dependent on the maturity of osteoblastic cells. Truncated MEPE (ASARM removed) or AC-100 enhanced the adhesion, spreading, and focal complex formation of unadhered osteoblastic cells leading to increased differentiation and bone formation after 28 days of culture. Furthermore, addition of truncated MEPE or AC-100 to mature osteoblasts had no significant effect on bone formation. Our data supports an action for truncated MEPE and AC-100 in altering the physiology of immature poorly adherent cells which subsequently influences the way in which these cells interact with a substrate to facilitate their survival and/or commitment to the osteoblast lineage.

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A fragment of the hypophosphatemic factor, MEPE, requires inducible cyclooxygenase‐2 to exert potent anabolic effects on normal human marrow osteoblast precursors

Cited by 20 publications

References 30 publications

Determination of Dual Effects of Parathyroid Hormone on Skeletal Gene Expression in Vivo by Microarray and Network Analysis

Determination of Dual Effects of Parathyroid Hormone on Skeletal Gene Expression in Vivo by Microarray and Network Analysis

Molecular Regulation of Matrix Extracellular Phosphoglycoprotein Expression by Bone Morphogenetic Protein-2

ASARM‐truncated MEPE and AC‐100 enhance osteogenesis by promoting osteoprogenitor adhesion

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