Roles of DMP1 Processing in Osteogenesis, Dentinogenesis and Chondrogenesis

Abstract

Dentin matrix protein 1 (DMP1) is an acidic protein that plays critical roles in osteogenesis and dentinogenesis. Protein chemistry studies have demonstrated that DMP1 primarily exists as processed NH<sub>2</sub>- and COOH-terminal fragments in the extracellular matrix of bone and dentin. Our earlier work showed that the substitution of Asp<sup>213</sup> (a residue at a cleavage site) by Ala<sup>213</sup> blocks the processing of mouse DMP1 in vitro. Recently, we generated transgenic mice expressing this mutant DMP1 (designated ‘D213A-DMP1’). By crossbreeding these transgenic mice with <i>Dmp1</i>-knockout (<i>Dmp1</i>-KO) mice, we obtained mice expressing the D213A-DMP1 transgene in the <i>Dmp1</i>-null background (named ‘<i>Dmp1</i>-KO/<i>D213A-Tg’</i> mice). In this study, we analyzed the long bone, mandible, dentin, and cartilage of <i>Dmp1-</i>KO/<i>D213A-Tg</i> mice in comparison with wild-type,<i> Dmp1</i>-KO, and <i>Dmp1</i>-KO mice expressing the normal DMP1 transgene (<i>Dmp1</i>-KO/normal-Tg). Our results showed that D213A-DMP1 was barely cleaved in the dentin matrix of <i>Dmp1</i>-KO/<i>D213A-Tg</i> mice and the expression of D213A-DMP1 failed to rescue the developmental defects in <i>Dmp1</i>-null mice. Interestingly, enlarged growth plates and condylar cartilages were observed in <i>Dmp1</i>-KO/<i>D213A-Tg</i> mice, indicating a potential role of the full-length form of DMP1 in chondrogenesis.