The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa c-terminal fragment
Open Access
- 23 August 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Bone and Mineral Research
- Vol. 26 (2), 331-340
- https://doi.org/10.1002/jbmr.226
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.Keywords
This publication has 40 references indexed in Scilit:
- Molecular analysis of DMP1 mutants causing autosomal recessive hypophosphatemic ricketsBone, 2009
- The NH2-terminal and COOH-terminal Fragments of Dentin Matrix Protein 1 (DMP1) Localize Differently in the Compartments of Dentin and Growth Plate of BoneJournal of Histochemistry & Cytochemistry, 2008
- MEPE-ASARM Peptides Control Extracellular Matrix Mineralization by Binding to Hydroxyapatite: An Inhibition Regulated by PHEX Cleavage of ASARMJournal of Bone and Mineral Research, 2008
- Studies of the DMP1 57-kDa Functional Domain both in vivo and in vitroCells Tissues Organs, 2008
- Distinct Compartmentalization of Dentin Matrix Protein 1 Fragments in Mineralized Tissues and CellsCells Tissues Organs, 2008
- Identification of Full-Length Dentin Matrix Protein 1 in Dentin and BoneCalcified Tissue International, 2008
- Rescue of odontogenesis in Dmp1-deficient mice by targeted re-expression of DMP1 reveals roles for DMP1 in early odontogenesis and dentin apposition in vivoDevelopmental Biology, 2007
- Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolismNature Genetics, 2006
- Osteomalacia in Hyp Mice Is Associated with Abnormal Phex Expression and with Altered Bone Matrix Protein Expression and DepositionEndocrinology, 2001
- Developmental Expression and Tissue Distribution of Phex Protein: Effect of the Hyp Mutation and Relationship to Bone MarkersJournal of Bone and Mineral Research, 2000