Cooperative effects in differentiation and proliferation between PDGF-BB and matrix derived synthetic peptides in human osteoblasts

Wähnert, Dirk; Paletta, Jürgen R. J.; Hartensuer, René; Pap, Thomas; Raschke, Michael J.; Ochman, Sabine

doi:10.1186/1471-2474-12-263

Cited by 24 publications

(27 citation statements)

References 39 publications

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“…The dentonin/AC100 peptide is a strong stimulator of bone/teeth formation in vitro and in vivo. 77,78,80–83,195–197 This contrasts with the ASARM peptide, an inhibitor of mineralization in vitro and in vivo (minhibin). 23–26, 29,31–33,39,86,88,89 …”

Section: Figurementioning

confidence: 97%

Regulation of Bone−Renal Mineral and Energy Metabolism: The PHEX, FGF23, DMP1, MEPE ASARM Pathway

Rowe

2012

Crit Rev Eukar Gene Expr

143

110

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More than 300 million years ago, vertebrates emerged from the vast oceans to conquer gravity and the dry land. With this transition, new adaptations occurred that included ingenious changes in reproduction, waste secretion, and bone physiology. One new innovation, the egg shell, contained an ancestral protein (ovocleidin-116) that likely first appeared with the dinosaurs and was preserved through the theropod lineage in modern birds and reptiles. Ovocleidin-116 is an avian homolog of matrix extracellular phosphoglycoprotein (MEPE) and belongs to a group of proteins called short integrin-binding ligand-interacting glycoproteins (SIBLINGs). These proteins are all localized to a defined region on chromosome 5q in mice and chromosome 4q in humans. A unifying feature of SIBLING proteins is an acidic serine aspartate-rich MEPE-associated motif (ASARM). Recent research has shown that the ASARM motif and the released ASARM peptide have regulatory roles in mineralization (bone and teeth), phosphate regulation, vascularization, soft-tissue calcification, osteoclastogenesis, mechanotransduction, and fat energy metabolism. The MEPE ASARM motif and peptide are physiological substrates for PHEX, a zinc metalloendopeptidase. Defects in PHEX are responsible for X-linked hypophosphatemic rickets (HYP). There is evidence that PHEX interacts with another ASARM motif containing the SIBLING protein, dentin matrix protein-1 (DMP1). DMP1 mutations cause bone and renal defects that are identical with the defects caused by a loss of PHEX function. This results in autosomal recessive hypophosphatemic rickets (ARHR). In both HYP and ARHR, increased FGF23 expression plays a major role in the disease and in autosomal dominant hypophosphatemic rickets (ADHR), FGF23 half-life is increased by activating mutations. ASARM peptide administration in vitro and in vivo also induces increased FGF23 expression. FGF23 is a member of the fibroblast growth factor (FGF) family of cytokines, which surfaced 500 million years ago with the boney fish (i.e., teleosts) that do not contain SIBLING proteins. In terrestrial vertebrates, FGF23, like SIBLING proteins, is expressed in the osteocyte. The boney fish, however, are an-osteocytic, so a physiological bone-renal link with FGF23 and the SIBLINGs was cemented when life ventured from the oceans to the land during the Triassic period, approximately 300 million years ago. This link has been revealed by recent research that indicates a competitive displacement of a PHEX–DMP1 interaction by an ASARM peptide that leads to increased FGF23 expression. This review discusses the new discoveries that reveal a novel PHEX, DMP1, MEPE, ASARM peptide, and FGF23 bone-renal pathway. This pathway impacts not only bone formation, bone-renal mineralization, and renal phosphate homeostasis but also energy metabolism. The study of this new pathway is relevant for developing therapies for several diseases: bone–teeth mineral loss disorders, renal osteodystrophy, chronic kidney disease and bone mineralization disorders (CKD-MBD), en...

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Section: Figurementioning

confidence: 97%

Regulation of Bone−Renal Mineral and Energy Metabolism: The PHEX, FGF23, DMP1, MEPE ASARM Pathway

Rowe

2012

Crit Rev Eukar Gene Expr

143

110

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“…350 Stimulation with TP-508 (500 μg/mL) exhibited a significant proliferative effect on human OB, especially within the early phase of cultivation. 284 Local administration of TP508 (100 μg) into the fracture gap has promoted bone formation and femoral fracture repair in a mouse model of high-energy fracture (model of delayed fracture healing). This was associated with reduced inflammation and enhanced angiogenesis in the surrounding soft tissues and in the fracture gap.…”

Section: H Tp-508 Designed From Thrombinmentioning

confidence: 99%

Short Anabolic Peptides for Bone Growth

Amso

Cornish²,

Brimble

2016

Medicinal Research Reviews

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Loss of bone occurs in the age-related skeletal disorder, osteoporosis, leading to bone fragility and increased incidence of fractures, which are associated with enormous costs and substantial morbidity and mortality. Recent data indicate that osteoporotic fractures are more common than other diseases, which usually attract public attention (e.g., heart attack and breast cancer). The prevention and treatment of this skeletal disorder are therefore of paramount importance. Majority of osteoporosis medications restore skeletal balance by reducing osteoclastic activity, thereby reducing bone resorption. These agents, however, do not regenerate damaged bone tissue, leaving limited options for patients once bone loss has occurred. Recently, attention has turned to bone-anabolic agents. Such agents have the ability to increase bone mass and strength, potentially reversing structural damage. To date, only one bone-anabolic drug is available in the market. The discovery of more novel, cost-effective bone anabolic agents is therefore a priority to treat those suffering from this disabling condition. Short peptides offer an important alternative for the development of novel bone-anabolic agents given their high target binding specificity, which translates into potent activity with limited side effects. This review summarizes attempts in the identification of bone-anabolic peptides, and their development for promoting bone growth.

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“…Species sequences for MEPE were searched for and downloaded from the “Ensembl” project resource at http://www.ensembl.org. The dentonin/AC100 peptide is a strong stimulator of bone/teeth formation in vitro and in vivo 80, 81, 83–86, 213–215 . This contrasts with the ASARM peptide, an inhibitor of mineralization in vitro and in vivo (minhibin) 31, 32, 34, 35, 37–39, 41, 47, 89, 91, 92 .…”

Section: Figurementioning

confidence: 99%

“…The dentonin/AC100 peptide is a strong stimulator of bone/teeth formation in vitro and in vivo. 80,81,[83][84][85][86][213][214][215] This contrasts with the acidic serine aspartate rich MEPE-associated motif peptide, an inhibitor of mineralization in vitro and in vivo (minhibin) 31,32,34,35,[37][38][39]41,47,89,91,92 Note that a DMP1 frame shift mutation ( Figure 11) results in the loss of the GD residues that are conserved in both MEPE and DMP1 and plays a key role in the binding kinetics and hydrolysis of PHEX to the ASARM region. 31,32 Recent experiments further support the notion that FGF23 is regulated through a PHEX-DMP1 common pathway involving FGF receptor signalling.…”

Section: The Asarm Model Bone-renal Mineralization and Phosphate Hommentioning

confidence: 99%

The chicken or the egg: PHEX, FGF23 and SIBLINGs unscrambled

Rowe

2012

Cell Biochemistry & Function

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The eggshell is an ancient innovation that helped the vertebrates’ transition from the oceans and gain dominion over the land. Coincident with this conquest several new eggshell and noncollagenous bone-matrix proteins (NCPs) emerged. The protein ovocleidin-116 is one of these proteins with an ancestry stretching back to the Triassic. Ovocleidin-116 is an avian homolog of Matrix Extracellular Phosphoglycoprotein (MEPE) and belongs to a group of proteins called Small Integrin-Binding Ligand Interacting Glycoproteins (SIBLINGs). The genes for these NCPs are all clustered on chromosome 5q in mice and chromosome 4q in humans. A unifying feature of the SIBLING proteins is an Acidic Serine Aspartate Rich MEPE associated motif (ASARM). The ASARM motif and the released ASARM peptide play roles in mineralization, bone turnover, mechanotransduction, phosphate regulation and energy metabolism. ASARM peptides and motifs are physiological substrates for PHEX, a Zn metalloendopeptidase. Defects in PHEX are responsible for X-linked hypophosphatemic rickets. PHEX interacts with another ASARM motif containing SIBLING protein, Dentin Matrix Protein-1 (DMP1). DMP1 mutations cause bone-renal defects that are identical with the defects caused by loss of PHEX function. This results in autosomal recessive hypophosphatemic rickets (ARHR). In both XLH and ARHR increased FGF23 expression occurs and activating mutations in FGF23 cause autosomal dominant hypophosphatemic rickets (ADHR). ASARM peptide administration in vitro and in vivo also induces increased FGF23 expression. This review will discuss the evidence for a new integrative pathway involved in bone formation, bone-renal mineralization, renal phosphate homeostasis and energy metabolism in disease and health.

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Cooperative effects in differentiation and proliferation between PDGF-BB and matrix derived synthetic peptides in human osteoblasts

Cited by 24 publications

References 39 publications

Regulation of Bone−Renal Mineral and Energy Metabolism: The PHEX, FGF23, DMP1, MEPE ASARM Pathway

Regulation of Bone−Renal Mineral and Energy Metabolism: The PHEX, FGF23, DMP1, MEPE ASARM Pathway

Short Anabolic Peptides for Bone Growth

The chicken or the egg: PHEX, FGF23 and SIBLINGs unscrambled

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