Abstract
Dentin matrix protein 1 (DMP-1) is a key molecule in controlling osteocyte formation and phosphate homeostasis. Based on observations that full-length DMP-1 is not found in bone, but only cleaved fragments of 37 and 57 kDa are present, and in view of the finding that mutations in the 57-kDa fragment result in disease, we hypothesized that the 57-kDa C-terminal fragment is the functional domain of DMP-1. To test this hypothesis, a 3.6-kb type I collagen promoter was used to express this 57-kDa C-terminal fragment for comparison with full-length DMP-1 in Dmp1 null osteoblasts/osteocytes. Not only did expression of the full-length DMP-1 in bone cells fully rescue the skeletal abnormalities of Dmp1 null mice, but the 57-kDa fragment also had similar results. This included rescue of growth plate defects, osteomalacia, abnormal osteocyte maturation, and the abnormal osteocyte lacunocanalicular system. In addition, the abnormal fibroblast growth factor 23 (FGF-23) expression in osteocytes, elevated circulating FGF-23 levels, and hypophosphatemia were rescued. These results show that the 57-kDa C-terminal fragment is the functional domain of DMP-1 that controls osteocyte maturation and phosphate metabolism. © 2011 American Society for Bone and Mineral Research.
Highlights
Dentin matrix protein 1 (DMP-1) is expressed predominantly in odontoblasts in tooth and osteocytes in bone.[1,2,3] Deletion of murine Dmp1 causes striking defects in tooth and bone during postnatal development in C57/B6 or CD-1 background mice.[4,5] Recently, we and others have demonstrated that DMP1 mutations result in autosomal recessive hypophosphatemic rickets (ARHR) in humans similar to the phenotype of Dmp1 null mice
This condition is characterized by rickets and the presence of large amounts of osteoid in bone and is accompanied by elevated circulating fibroblast growth factor 23 (FGF-23).(6–9) Using the Dmp1 null mouse as a model for human ARHR, we found that Dmp1 null osteocytes express elevated FGF-23, suggesting that Dmp1 might be a negative regulator of FGF-23 expression during bone development.[6]
FGF-23 is a potent phosphaturic hormone expressed predominantly by osteocytes in bone[6,10,11,12] that target the kidney to promote renal excretion of phosphate.[13,14] In addition, PHEX has been shown to regulate FGF-23 expression in bone.[12]. PHEX is predominantly expressed in osteoblasts and osteocytes.[15]. PHEX mutations in mice and humans result in autosomal dominant hypophosphatemic rickets (ADHR), accompanied by elevated circulating FGF-23, a phenotype similar to that of Dmp1 null mice.[6,10] Taken together, these observations suggest that elevated circulating FGF-23 and hypophosphatemia are pathogenic factors involved in both Phex and Dmp1 mutant mice
Summary
Dentin matrix protein 1 (DMP-1) is expressed predominantly in odontoblasts in tooth and osteocytes in bone.[1,2,3] Deletion of murine Dmp causes striking defects in tooth and bone during postnatal development in C57/B6 or CD-1 background mice.[4,5] Recently, we and others have demonstrated that DMP1 mutations result in autosomal recessive hypophosphatemic rickets (ARHR) in humans similar to the phenotype of Dmp null mice. It was discovered that a DMP1 mutation, which results in replacement of the last 18 amino acid residues with 33 novel residues, results in ARHR.[6,7] In vitro studies showed that this mutant DMP-1 is secreted and processed into the 37-kDa N-terminal fragment and the mutant 57-kDa fragment,(6) suggesting that patients should have normal 37-kDa fragment expression These observations suggest that the 57-kDa fragment might be the key functional domain of DMP-1. Our study shows that the 57-kDa fragment recapitulates the function of full-length DMP-1 in regulation of mineralization and osteocyte maturation and highlights the molecular mechanisms responsible for hypophosphatemic rickets
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
