Isolation of mitogenically active C‐terminal truncated pentapeptide of osteogenic growth peptide from human plasma and culture medium of murine osteoblastic cells

I, Bab; Gavish, Hanna; Namdar-Attar, M; Mühlrád, András; Greenberg, Zvi; Chen, Y; Mansur, Nora; Shteyer, A.; Chorev, Michael

doi:10.1034/j.1399-3011.1999.00135.x

Cited by 30 publications

(38 citation statements)

References 15 publications

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“…As shown in Fig. 5B, OGP-(10 -14) had a biphasic effect on luciferase activity in the MC3T3 E1/CRE-luc cells, with the maximum stimulation observed at 10 Ϫ14 M. This bell-shaped curve is reminiscent of the OGP-(10 -14) dose-response curve observed when DNA synthesis is measured (14). The OGP-(10 -14) stimulation of CREB transcriptional activ- ity was mitigated dose-dependently by the MEK-ERK1/2 inhibitor PD098059 (Fig.…”

Section: Mapkapk2 Mediates the Mitogenic Effect Of Ogp-(10 -14)-mentioning

confidence: 69%

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ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

Miguel

Namdar-Attar

Noh

et al. 2005

Journal of Biological Chemistry

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In osteoblasts, the mitogen-activated protein kinases ERK1/2 and p38 as well as the cAMP-response element-binding protein (CREB) have been implicated in the regulation of proliferation and differentiation. The osteogenic growth peptide (OGP) is a 14-mer bone cell mitogen that increases bone formation and trabecular bone density and stimulates fracture healing. OGP-(10 -14) is the physiologically active form of OGP. Using gene array analysis, real-time reverse transcription-PCR, and immunoblot and DNA synthesis assays we show here that in MC3T3 E1 and newborn mouse calvarial osteoblastic cultures the OGP-(10 -14) mitogenic signaling is critically dependent on de novo synthesis of mitogen-activated protein kinase-activated protein kinase 2 (Mapkapk2) mRNA and protein.The increase in Mapkapk2 occurs following short term (5-60 min) stimulation of ERK1/2 activity by OGP-(10 -14); phosphorylation of p38 remains unaffected. Downstream of Mapkapk2, CREB is phosphorylated on Ser 133 leading to its enhanced transcriptional activity. That these events are critical for the OGP-(10 -14) mitogenic signaling is demonstrated by blocking the effects of OGP-(10 -14) on the ERK1/2 pathway, Mapkapk2, CREB, and DNA synthesis using the MEK inhibitor PD098059. The OGP-(10 -14) stimulation of CREB transcriptional activity and DNA synthesis is also blocked by Mapkapk2 siRNA. These data define a novel mitogenic signaling pathway in osteoblasts whereby ERK1/2 stimulation of CREB phosphorylation and transcriptional activity as well as DNA synthesis are critically dependent on de novo Mapkapk2 synthesis.In mammalian cells, the family of mitogen-activated protein (MAP) 3 kinases provides a key link between membrane-bound receptors and changes in the pattern of gene expression. The MAP kinases are activated downstream of many different types of receptors, including tyrosine kinase receptors, cytokine receptors, and serpentine G-protein coupled receptors (1, 2). The MAP kinases consist of four subfamilies: the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase/stress-activated kinase, p38 MAP kinase, and ERK 5. Further downstream, they regulate a multitude of transcription factors that control cell proliferation, survival, and differentiation (3, 4). In osteoblasts, ERK1/2-dependent phosphorylation cascades have been implicated in the regulation of proliferation and RUNX2 activity (5, 6). Activation of p38 has been demonstrated in osteoblasts undergoing differentiation after stimulation with bone morphogenetic protein-2 and epidermal growth factor (7,8).The osteogenic growth peptide (OGP) is a 14-mer bone cell mitogen that increases bone formation and trabecular bone density and stimulates fracture healing when administered to mice and rats (9 -11). Transgenic mice overexpressing OGP have a markedly increased peak bone mass (12). OGP is present in mammalian serum in micromolar concentrations mainly complexed to ␣ 2 -macroglobulin (13). Upon its dissociation from the complex, it is proteolytically activated yieldin...

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Section: Mapkapk2 Mediates the Mitogenic Effect Of Ogp-(10 -14)-mentioning

confidence: 69%

“…OGP is present in mammalian serum in micromolar concentrations mainly complexed to ␣ 2 -macroglobulin (13). Upon its dissociation from the complex, it is proteolytically activated yielding the mitogenic C-terminal pentapeptide OGP-(10 -14) (14). In addition to stimulating bone formation, OGP-(10 -14) potently enhances hematopoiesis (15,16).…”

mentioning

confidence: 99%

ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

Miguel

Namdar-Attar

Noh

et al. 2005

Journal of Biological Chemistry

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“…Up to now, different types of osteoinductive peptides have been proposed [4]. In this study, we evaluated the potential of OGP, a naturally occurring tetradeca-peptide identical to the C-terminus of histone H4 (residues 89-102, ALKRQGRTLYGFGG), which is present in plasma at micromolar concentrations [5][6][7][8]. The physiologically active form of OGP, which corresponds to its C-terminal pentapeptide sequence YGFGG (OGP10-14), is generated from full-length OGP by proteolytic cleavage [5].…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we evaluated the potential of OGP, a naturally occurring tetradeca-peptide identical to the C-terminus of histone H4 (residues 89-102, ALKRQGRTLYGFGG), which is present in plasma at micromolar concentrations [5][6][7][8]. The physiologically active form of OGP, which corresponds to its C-terminal pentapeptide sequence YGFGG (OGP10-14), is generated from full-length OGP by proteolytic cleavage [5]. This fragment directly interacts with cell membrane receptors, activating the MAP kinase, Src and RhoA signaling pathways [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Hydrogel depots for local co-delivery of osteoinductive peptides and mesenchymal stem cells

Maia

Barbosa²,

Gomes

et al. 2014

Journal of Controlled Release

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The outcome of cell-based therapies can benefit from carefully designed cell carriers. A multifunctional injectable vehicle for the co-delivery of human mesenchymal stem cells (hMSCs) and osteoinductive peptides is proposed, to specifically direct hMSCs osteogenic differentiation. The osteogenic growth peptide (OGP) inspired the design of two peptides, where the bioactive portion of OGP was flanked by a protease-sensitive linker, or its scrambled sequence, to provide faster and slower release rates, respectively. Peptides were fully characterized and chemically grafted to alginate. Both OGP analogs released bioactive fragments in vitro, at different kinetics, which stimulated hMSCs proliferation and osteogenesis. hMSCs-laden OGP-alginate hydrogels were tested at an ectopic site in a xenograft mouse model. After 4 weeks, OGP-alginate hydrogels were more degraded and colonized by vascularized connective tissue than the control (without OGP). hMSCs were able to proliferate, migrate outward the hydrogels, produce endogenous extracellular matrix and mineralize it. Moreover, OGP-groups stimulated hMSCs osteogenesis, as compared with the control. Overall, the ability of the proposed platform to direct the fate of transplanted hMSCs in loco was demonstrated, and OGP-releasing hydrogels emerged as a potentially useful system to promote bone regeneration.

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“…A recent study has used an expressed BMP-2 peptide containing 102 amino acids of the C-terminal end of the molecule to induce bone formation, 22 and others have studied the osteogenic growth peptide, which is a positively charged 14-amino acid growth polypeptide generated as a posttranslational cleavage product using an alternative translational initiation codon of the histone H4 gene. [23][24][25] Therefore, the present study sought to identify the minimal bioactive sequences from BMP-7 for potential immobilization on biomaterials and use in control of osteoblast functions.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Mineralization Studies with Substrate-immobilized Bone Morphogenetic Protein Peptides

Kirkwood¹,

Rheude²,

Kim³

et al. 2003

Journal of Oral Implantology

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Understanding the factors that control osteoblastic behavior is centrally important in establishment of successful osseointegration. Pharmacogenetic control of the osteoblast to increase the mineral content around dental implants may offer a unique advantage to clinicians in improving osseointegration success and decreasing time before mechanical loading. This in vitro pilot study has screened for bioactive peptides derived from bone morphogenetic protein 7 (BMP-7) (also called osteogenic protein 1 [OP-1]). Thirteen overlapping peptides of BMP-7 were synthesized and covalently coupled to glass coverslip substrates using silane chemistry. The rate and relative amount of mineralization were compared by von Kossa analysis using primary rat calvarial osteoblastic cell populations during a 7-to 21-day period. In addition, bone sialoprotein (BSP) and osteocalcin (OC) gene expression was measured from osteoblastic cells grown on peptide-immobilized glass coverslips by reverse transcriptase-polymerase chain reaction. Initial results from mineralization studies suggested the BMP-7-derived peptides were able to support mineralization to varying degrees with enhanced peptide-induced mineralization from the C-and N-termini of the BMP-7 molecule. Analysis of these peptide regions indicated that these peptides comprised the finger 1 and 2 domains of OP-1, which contribute toward ligand-receptor interaction. Further analysis of gene expression from select peptide-immobilized substrates indicated that peptides from the C-terminus of BMP-7 were capable of supporting BSP and OC messenger RNA expression. These studies indicate that BMP-7 peptides covalently bound to solid substrates may provide the biological basis to immobilize peptides to titanium implants to induce osteoblastic differentiation and mineralization in a more predictable fashion.

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Isolation of mitogenically active C‐terminal truncated pentapeptide of osteogenic growth peptide from human plasma and culture medium of murine osteoblastic cells

Cited by 30 publications

References 15 publications

ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

ERK1/2-activated de Novo Mapkapk2 Synthesis Is Essential for Osteogenic Growth Peptide Mitogenic Signaling in Osteoblastic Cells

Hydrogel depots for local co-delivery of osteoinductive peptides and mesenchymal stem cells

In Vitro Mineralization Studies with Substrate-immobilized Bone Morphogenetic Protein Peptides

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