Hypophosphatemic rickets accelerate chondrogenesis and cell trans-differentiation from TMJ chondrocytes into bone...

Dentin matrix protein 1 (DMP1) is primarily expressed in osteocytes, although a low level of DMP1 is also detected in chondrocytes. Removing Dmp1 in mice or a mutation in humans leads to hypophosphatemic rickets (identical to X-linked hypophosphatemia). The deformed skeletons were currently thought to be a consequence of an inhibition of chondrogenesis (leading to an accumulation of hypertrophic chondrocytes and a failure in the replacement of cartilage by bone). To precisely study the mechanisms by which DMP1 and phosphorus control temporomandibular condyle formation, we first showed severe malformed condylar phenotypes in Dmp1-null mice (great expansions of deformed cartilage layers and subchondral bone), which worst as aging. Next, we excluded the direct role of DMP1 in condylar hypertrophic-chondrogenesis by conditionally deleting Dmp1 in hypertrophic chondrocytes using Col10a1-Cre and Dmp1 loxP mice (displaying no apparent phosphorous changes and condylar phenotype). To address the mechanism by which the onset of endochondral phenotypes takes place, we generated two sets of tracing lines in the Dmp1 KO background: AggrecanCreERT2-ROSA-tdTomato and Col 10a1-Cre-ROSA-tdTomato, respectively. Both tracing lines displayed an acceleration of chondrogenesis and cell trans-differentiation from chondrocytes into bone cells in the Dmp1 KO. Next, we showed that administrations of neutralizing fibroblast growth factor 23 (FGF23) antibodies in Dmp1-null mice restored hypophosphatemic condylar cartilage phenotypes. In further addressing the rescue mechanism, we generated compound mice containing Col10a1-Cre with ROSA-tdTomato and Dmp1 KO lines with and without a high Pi diet starting at day 10 for 39 days. We demonstrated that hypophosphatemia leads to an acceleration of chondrogenesis and trans-differentiation of chondrocytes to bone cells, which were largely restored under a high Pi diet. Finally, we identified the causative molecule (β-catenin). Together, this study demonstrates that the Dmp1-null caused hypophosphatemia, leading to acceleration (instead of inhibition) of chondrogenesis and bone trans-differentiation from chondrocytes but inhibition of bone cell maturation due to a sharp increase in β-catenin. These findings will aid in the future treatment of hypophosphatemic rickets with FGF23 neutralizing antibodies.