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Lorenz-Depiereux, B. et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat. Genet. 38, 1248-1250

Institute of Human Genetics, GSF National Research Center for Environment and Health, 85764 Munich-Neuherberg, Germany.
Nature Genetics (Impact Factor: 29.65). 12/2006; 38(11):1248-50. DOI: 10.1038/ng1868
Source: PubMed

ABSTRACT Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.

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    • "DMP1 is a multifunctional protein involved in the biomineralization of bones and dentin (Ling et al., 2005; Lu et al., 2007; Qin et al., 2004), phosphate homeostasis (Feng et al., 2006), and differentiation of odonto-and osteoblasts (Almushayt et al., 2006; Narayanan et al., 2001). Mutations in this gene cause autosomal recessive hypophosphatemic rickets syndrome , manifested by rickets and osteomalacia with isolated renal phosphate-wasting (Feng et al., 2006; Lorenz-Depiereux et al., 2006). DMP1 belongs to the SIBLING (Small Intergrin Binding Nlinked Glicoproteins) family, which are associated with mineralized tissues (Fisher and Fedarko, 2003), although they were found in other tissues as well (Fisher et al., 2004; Ogbureke and Fisher, 2005). "
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    • "DMP1 is a multifunctional protein involved in the biomineralization of bones and dentin (Ling et al., 2005; Lu et al., 2007; Qin et al., 2004), phosphate homeostasis (Feng et al., 2006), and differentiation of odonto-and osteoblasts (Almushayt et al., 2006; Narayanan et al., 2001). Mutations in this gene cause autosomal recessive hypophosphatemic rickets syndrome, manifested by rickets and osteomalacia with isolated renal phosphate-wasting (Feng et al., 2006; Lorenz-Depiereux et al., 2006). DMP1 belongs to the SIBLING (Small Intergrin Binding N-linked Glicoproteins) family, which are associated with mineralized tissues (Fisher and Fedarko, 2003), although they were found in other tissues as well (Fisher et al., 2004; Ogbureke and Fisher, 2005). "
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    ABSTRACT: Dentin Matrix Protein 1 (DMP1), the essential noncollagenous proteins in dentin and bone, is believed to play an important role in the mineralization of these tissues, although the mechanisms of its action are not fully understood. To gain insight into DMP1 functions in dentin mineralization we have performed immunomapping of DMP1 in fully mineralized rat incisors and in vitro calcium phosphate mineralization experiments in the presence of DMP1. DMP1 immunofluorescene was localized in peritubular dentin (PTD) and along the dentin-enamel boundary. In vitro phosphorylated DMP1 induced the formation of parallel arrays of crystallites with their c-axes co-aligned. Such crystalline arrangement is a hallmark of mineralized collagen fibrils of bone and dentin. Interestingly, in DMP1-rich PTD, which lacks collagen fibrils, the crystals are organized in a similar manner. Based on our findings we hypothesize, that in vivo DMP1 controls the mineral organization outside of the collagen fibrils and plays a major role in the mineralization of PTD.
    Journal of Structural Biology 11/2010; 174(1):100-6. DOI:10.1016/j.jsb.2010.11.013 · 3.23 Impact Factor
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    • "Along with low P i levels, these patients and murine homologues exhibit osteomalacia, expanded alveolar bone, increased predentin/dentin ratio, interglobular dentin, and enlarged pulp chambers (Abe et al., 1989; Feng et al., 2006; Liu et al., 2006; Murayama et al., 2000; Ye et al., 2004). The skeletal and tooth abnormalities associated with low P i have been associated with an excess of serum fibroblast growth factor 23 (FGF23), a hormone discovered in patients with tumor induced osteomalacia (TIO), another P i wasting disorder (ADHR_Consortium, 2000; Liu et al., 2006; Liu et al., 2008; Lorenz-Depiereux et al., 2006; Shimada et al., 2001; Sitara et al., 2004). FGF23 production has been localized predominantly to osteocytes, with lower levels noted in osteoblasts and cementoblasts (Quarles, 2003; Riminucci et al., 2003; Yoshiko et al., 2007). "
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    ABSTRACT: Fibroblast growth factor-23 (FGF23) is a hormone that modulates circulating phosphate (P(i)) levels by controlling P(i) reabsorption from the kidneys. When FGF23 levels are deficient, as in tumoral calcinosis patients, hyperphosphatemia ensues. We show here in a murine model that Fgf23 ablation disrupted morphology and protein expression within the dentoalveolar complex. Ectopic matrix formation in pulp chambers, odontoblast layer disruption, narrowing of periodontal ligament space, and alteration of cementum structure were observed in histological and electron microscopy sections. Because serum P(i) levels are dramatically elevated in Fgf23(-/-), we assayed for apoptosis and expression of members from the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, both of which are sensitive to elevated P(i) in vitro. Unlike X-linked hypophosphatemic (Hyp) and wild-type (WT) specimens, numerous apoptotic osteocytes and osteoblasts were detected in Fgf23(-/-) specimens. Further, in comparison to Hyp and WT samples, decreased bone sialoprotein and elevated dentin matrix protein-1 protein levels were observed in cementum of Fgf23(-/-) mice. Additional dentin-associated proteins, such as dentin sialoprotein and dentin phosphoprotein, exhibited altered localization in both Fgf23(-/-) and Hyp samples. Based on these results, we propose that FGF23 and (P(i)) homeostasis play a significant role in maintenance of the dentoalveolar complex.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 07/2010; 293(7):1214-26. DOI:10.1002/ar.21152 · 1.53 Impact Factor
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