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Hypophosphatemic rickets accelerate chondrogenesis and cell trans-differentiation from TMJ chondrocytes into bone cells via a sharp increase in ?-catenin.

ABSTRACT: 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 (?-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 ?-catenin. These findings will aid in the future treatment of hypophosphatemic rickets with FGF23 neutralizing antibodies.

SUBMITTER: Li H

PROVIDER: S-EPMC6930687 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Hypophosphatemic rickets accelerate chondrogenesis and cell trans-differentiation from TMJ chondrocytes into bone cells via a sharp increase in β-catenin.

Li Hui H Jing Yan Y Zhang Rong R Zhang Qi Q Wang Jun J Martin Aline A Feng Jian Q JQ

Bone 20191118

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 mechanism ...[more]

PMID: 31751752

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Project description:We previously demonstrated that the mutations Met1Val (M1V) and the deletion of nucleotides 1484-1490 (1484-1490del) in Dentin matrix protein-1 (DMP1) cause the novel disorder autosomal recessive hypophosphatemic rickets (ARHR), which is associated with elevated fibroblast growth factor-23 (FGF23). To further understand the role of DMP1 in ARHR, we undertook molecular genetic and in vitro expression studies. First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance. Analyses of this family demonstrated that the affected members had elevated serum FGF23 and carried a large, biallelic deletion that removed the majority of DMP1. At a minimum, this deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5' to the next telomeric gene, integrin-binding sialoprotein (IBSP). We next performed immunofluorescent studies in cells to understand the effects of the known ARHR mutations on DMP1 cellular processing. These analyses showed that the M1V DMP1 mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, but filled the entire cytoplasm. In contrast, the 1484-1490del mutant localized to the TGN and was secreted, similar to wild type DMP1. The 1484-1490del mutation replaces the DMP1 18 C-terminal amino acids with 33 non-native residues. Truncation of wild type DMP1 by these native 18 residues followed by Western blot and confocal microscopic analyses demonstrated a wild type expression pattern when compared with the 1484-1490del mutant, indicating that the last 18 residues are not critical for cellular trafficking, but that the 33 additional residues arising from the 1484-1490del mutation likely compromise DMP1 processing. The relationship between DMP1 and FGF23 is unclear. To test endogenous DMP1 response to serum metabolites that also regulate FGF23, UMR-106 cells were treated with 1,25(OH)(2) vitamin D (1x10(-7) M) and showed a 12-fold increase in DMP1 mRNA and protein at 24 h. In summary, we have identified a novel DMP1 deletion as the cause of ARHR, as well as demonstrated that the ARHR mutations alter DMP1 cellular processing, and that DMP1 can be regulated by vitamin D. Taken together, this work expands our understanding of the genetic and molecular mechanisms associated with DMP1 alterations causing ARHR.

Dataset Information

Hypophosphatemic rickets accelerate chondrogenesis and cell trans-differentiation from TMJ chondrocytes into bone cells via a sharp increase in ?-catenin.

Publications

Hypophosphatemic rickets accelerate chondrogenesis and cell trans-differentiation from TMJ chondrocytes into bone cells via a sharp increase in β-catenin.

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