Parathyroid hormone-related protein: an essential physiological regulator of adult bone mass.
- SourceAvailable from: Enrique Gómez-Barrena[Show abstract] [Hide abstract]
ABSTRACT: Current data suggest that parathyroid hormone (PTH)-related peptide (PTHrP) domains other than the N-terminal PTH-like domain contribute to its role as an endogenous bone anabolic factor. PTHrP-107-139 inhibits bone resorption, a fact which has precluded an unequivocal demonstration of its possible anabolic action in vivo. We thus sought to characterize the osteogenic effects of this peptide using a mouse model of diabetic low-turnover osteopaenia. PTHrP-107-139 was administered to streptozotocin-induced diabetic mice, with or without bone marrow ablation, for 13 days. Osteopaenia was confirmed by dual-energy X-ray absorptiometry and microcomputed tomography analysis. Histological analysis was performed on paraffin-embedded bone tissue sections by haematoxylin/eosin and Masson's staining, and tartrate-resistent acid phosphatase immunohistochemistry. Mouse bone marrow stromal cells and osteoblastic MC3T3-E1 cells were cultured in normal and/or high glucose (HG) medium. Osteogenic and adipogenic markers were assessed by real-time PCR, and PTHrP and the PTH(1) receptor protein expression by Western blot analysis. PTHrP-107-139 reversed the alterations in bone structure and osteoblast function, and also promoted bone healing after marrow ablation without affecting the number of osteoclast-like cells in diabetic mice. This peptide also reversed the high-glucose-induced changes in osteogenic differentiation in both bone marrow stromal cells and the more differentiated MC3T3-E1 cells. These findings demonstrate that PTHrP-107-139 promotes bone formation in diabetic mice. This mouse model and in vitro cell cultures allowed us to identify various anabolic effects of this peptide in this scenario.British Journal of Pharmacology 03/2011; 162(6):1424-38. DOI:10.1111/j.1476-5381.2010.01155.x · 4.99 Impact Factor
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ABSTRACT: Type 1 diabetes mellitus (T1D) is associated with bone loss. Given that the Wnt/beta-catenin pathway is a major regulator of bone accrual, we assessed this pathway in mice with streptozotozin-induced T1D. In diabetic mouse long bones, we found alterations favouring the suppression of this pathway by using PCR arrays and beta-catenin immunostaining. Downregulation of sclerostin, an inhibitor of this pathway, also occurred, and related to increased osteocyte apoptosis. Our data show that both N- and C-terminal parathyroid hormone-related peptide fragments might exert osteogenic effects in this setting by targeting several genes of this pathway and increasing beta-catenin in osteoblastic cells.FEBS letters 07/2010; 584(14):3095-100. DOI:10.1016/j.febslet.2010.05.047 · 3.34 Impact Factor
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ABSTRACT: Parathyroid hormone-related protein (PTHrP) is an important regulator of bone remodeling. Recent studies show that this protein can induce osteogenic features through its N- and C-terminal domains. Silica-based ordered mesoporous bioceramics with an SBA-15 structure - known to be bioactive and biocompatible - have recently been evaluated for their capacity to uptake and deliver L-tryptophan. This amino acid corresponds to the end position of the 107-111 domain (called osteostatin) of the native C-terminal PTHrP (107-139) fragment, whose true action in bone metabolism is still ill-defined. In the present study, we assessed some effects of the aforementioned biomaterials pressed into disks, loaded or not with osteostatin, in osteoblastic cell cultures. Our data demonstrate that both unmodified and organically modified SBA-15 loaded with this peptide increase cell growth and the expression of several osteoblastic products (alkaline phosphatase, osteocalcin, collagen, osteoprotegerin, receptor activator of nuclear factor-kappaB ligand and vascular endothelial growth factor) in osteoblastic cells. These findings support the notion that osteostatin coating confers osteogenic features to silica-based ordered mesoporous materials, which make them suitable biomaterials for bone repair.Acta biomaterialia 09/2009; 6(3):797-803. DOI:10.1016/j.actbio.2009.08.033 · 5.68 Impact Factor