Dmp1 Null Mice Display Early Onset Periodontal Defects

OBJECTIVES: Recently, mutations in Dentin Matrix Protein 1 (DMP1), a matrix protein, has been shown to be responsible for hypophosphatemic rickets. Both Dmp1 null mice and patients with Autosomal Recessive Hypophosphatemic Rickets share a similar phenotype of osteomalacia and elevated circulating FGF23. We have previously reported the enlarged pulp chambers and increased predentin width in Dmp1 null mice, but little is known regarding the health of their periodontium.

METHODS: Dmp1 null and WT mice were sacrificed 3 weeks and 3 months of age. Radiology, histomorphometric analysis, fluorochrome labeling, scanning electron microscopy were used to study alveolar bone and cementum. TRAP staining, in vitro spleen cell culture, bone marrow cell culture, calvarial cell culture, and real-time PCR were used to evaluate osteoclast formation by osteoclast-supporting cells. In addition, transgenic mice expressing the DMP1 C-terminal 57kD transgene was expressed in Dmp1 null mice using the 3.6 kb Col 1 promoter to evaluate function.

RESULTS: Dmp1 null mice show early-onset periodontitis, with severe interproximal alveolar bone loss and pocket formation by 3 months of age. Moreover, Dmp1 null mice display immature and porous alveolar bone and abnormal cementum formation, which may be responsible for the periodontal defects. Although osteoclast number in alveolar bone in Dmp1 null mice is increased at 3 months, in vitro studies show that there is a defect in osteoblast/stromal cell support of osteoclast formation and function. Primary calvarial osteoblasts from Dmp1 null mice showed higher OPG and lower RANKL expression compared to wild-type cells. Finally, Re-expression of the DMP1 57kD C-terminal fragment fully rescued the periodontal defects in Dmp1 null mice, suggesting the C-terminal fragment is the functional domain of DMP1.

CONCLUSION: DMP1 plays important roles in cementogenesis and osteogenesis. Clinicians should be more proactive with regards to recognizing and treating hypophosphatemic patients (DE 016977 and AR51587)