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Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone
L Argiro1, M Desbarats, F H Glorieux
1Genetics Unit, Shriners Hospital, Montreal, Quebec, H3G 1A6, Canada.
Abstract:
The MEPE (matrix extracellular phosphoglycoprotein) gene is a strong candidate for the tumor-derived phosphaturic factor in oncogenic hypophosphatemic osteomalacia (OHO). X-linked hypophosphatemia (XLH) is phenotypically similar to OHO and results from mutations in PHEX, a putative metallopeptidase believed to process a factor(s) regulating bone mineralization and renal phosphate reabsorption. Here we report the isolation of the murine homologue of MEPE, from a bone cDNA library, that encodes a protein of 433 amino acids, 92 amino acids shorter than human MEPE. Mepe, like Phex, is expressed by fully differentiated osteoblasts and down-regulated by 1,25-(OH)2D3. In contrast to Phex, Mepe expression is markedly increased during osteoblast-mediated matrix mineralization. Greater than normal Mepe mRNA levels were observed in bone and osteoblasts derived from Hyp mice, the murine homologue of human XLH. Our data provide the first evidence that MEPE/Mepe is expressed by osteoblasts in association with mineralization.
Insights
Matrix extracellular phosphoglycoprotein (MEPE) is linked to oncogenic hypophosphatemic osteomalacia. This study identifies the murine MEPE homolog and shows its increased expression during bone mineralization in X-linked hypophosphatemia models.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- The matrix extracellular phosphoglycoprotein (MEPE) gene is a candidate for the phosphaturic factor in oncogenic hypophosphatemic osteomalacia (OHO).
- X-linked hypophosphatemia (XLH) shares similarities with OHO and involves mutations in PHEX, a metallopeptidase regulating phosphate homeostasis.
- PHEX is believed to process factors affecting bone mineralization and renal phosphate reabsorption.
Purpose of the Study:
- To isolate and characterize the murine homolog of the MEPE gene.
- To investigate the expression pattern of Mepe in osteoblasts and its association with mineralization.
- To examine Mepe expression in the murine model of XLH (Hyp mice).
Main Methods:
- Isolation of the murine MEPE homolog from a bone cDNA library.
- Analysis of Mepe protein and mRNA expression in osteoblasts.
- Comparison of Mepe expression in normal and Hyp mice.
Main Results:
- The murine MEPE homolog encodes a 433-amino acid protein, 92 amino acids shorter than human MEPE.
- Mepe is expressed by differentiated osteoblasts and down-regulated by 1,25-(OH)2D3.
- Mepe expression increases during osteoblast-mediated matrix mineralization, and elevated mRNA levels are found in Hyp mice.
Conclusions:
- MEPE/Mepe is expressed by osteoblasts in association with mineralization.
- This finding provides a link between MEPE and the pathophysiology of hypophosphatemic disorders.
- Further research into MEPE's role could elucidate mechanisms of phosphate regulation and bone mineralization.