DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis.
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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ABSTRACT: We previously reported that targeted overexpression of the Fibroblast Growth Factor 2 (FGF2) high molecular weight (HMW) isoforms in osteoblastic lineage cells in mice resulted in phenotypic changes, including dwarfism, rickets, osteomalacia, hypophosphatemia, increased serum parathyroid hormone (PTH) and increased levels of the phosphatonin FGF23 in serum and bone. The current study examined the effects of genetically knocking out the FGF2HMW isoforms (HMWKO) on bone and phosphate homeostasis. HMWKO mice were not dwarfed and had significantly increased bone mineral density and bone mineral content in femurs and lumbar vertebrae when compared to the wild type (WT) littermates. Micro-CT analysis of femurs revealed increased trabecular bone volume, thickness, number and connective tissue density with decreased trabecular spacing compared with WT. In addition, there was significantly decreased cortical porosity and increased cortical thickness and sub-periosteal area in femurs of HMWKO. Histomorphometric analysis demonstrated increased osteoblast activity and diminished osteoclast activity in the HMWKO. In vitro bone marrow stromal cell cultures showed there was a significant increase in alkaline phosphatase positive colony number at 1 week in HMWKO. At 3 weeks of culture, mineralized area was also significantly increased. There were increased expression of osteoblast differentiation marker genes and reduced expression of genes associated with impaired mineralization including a significant reduction in Fgf23 and Sost mRNA. Normal serum phosphate and PTH were observed in HMWKO mice. This study demonstrates a significant negative impact of HMWFGF2 on biological functions in bone and phosphate homeostasis in mice.Journal of Biological Chemistry 11/2014; 289(52). DOI:10.1074/jbc.M114.619569 · 4.60 Impact Factor
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ABSTRACT: Sepsis patients experience transient hypophosphataemia suggesting a role for FGF23.•TNF, TWEAK, IL-1β and LPS increased Fgf23 mRNA levels in osteocytes and bone.•TNF, TWEAK, IL-1β and LPS suppressed negative regulators of FGF23.•TNF and IL-1β caused secretion of C-term FGF23 but not intact FGF23.•Inhibition of furin proteases led to intact FGF23 secretion in response to TNF and IL-1β.Molecular and Cellular Endocrinology 01/2015; 399. DOI:10.1016/j.mce.2014.10.007 · 4.24 Impact Factor