An ancient legacy of life transitioning from oceans to land is the role of the skeleton and kidney in regulating mineralization and Ca/PO4 homeostasis. Key players in this bone kidney axis are a group of related extracellular matrix proteins (SIBLINGs). These proteins all map to a tightly clustered region on chromosome 4q. A unique protein PHEX, regulates at least two SIBLING proteins (MEPE and DMP1), indirectly or directly. PHEX is a zn-metalloendopeptidase in search of a substrate and may also play a role as an orphan ligand or receptor. Loss of PHEX function results in X-linked hypophosphatemic rickets and a novel cytokine FGF23 (a phosphatonin), plays a major role in the phosphate phenotype. Our data confirms direct binding of PHEX to MEPE, a SIBLING protein expressed in bone, teeth and in the proximal convoluted tubules of the kidney. The binding between these proteins occurs between the PHEX Zn-binding motif and a short COOH-terminal region of MEPE called the ASARM-motif. This short region is exquisitely resistant to proteolysis and conserved across species. Biologically, the released ASARM-peptide is a potent inhibitor of mineralization, inhibits renal phosphate handling and binds to hydroxyapatite. Binding of PHEX to MEPE may serve to regulate release of the ASARM peptide and thus locally control mineralization. PHEX also binds with high affinity to free ASARM- peptide and also inactivates the peptide by hydrolysis. In HYP, as well as a loss of PHEX function, there is a marked up regulation of MEPE and osteoblastic protease activity. This results in degradation of MEPE and DMP1 and release of ASARM-peptides from both these proteins and perhaps other SIBLING proteins (DSPP, osteopontin BSP, enamelin). These protease resistant ASARM-peptides accumulate in kidney, bone, urine and in the circulation. To study the role of SIBLINGs, PHEX and ASARM- peptides we have made transgenic mice (MEPE-TRG) that overexpress MEPE protein 50X in bone and 7X in kidney.
Our specific aims are: 1. Characterize bone and renal PO4 phenotypes of MEPE-TRG mice, 2. Determine the bone and renal- calcification roles of processed forms of MEPE and ASARM-peptides in MEPE-TRG, HYP and NPT2a-/- mice, 3. Design PHEX synthetic peptides as tools to probe the role of ASARM peptides and PHEX in health and disease.
A new class of recently discovered bone-teeth and renal proteins (SIBLINGs) play a major role in upholding the health of the skeleton and regulating phosphate. Bioactive processed peptides from these proteins impact on mineralization, bone formation, bone growth and soft tissue calcification in disease and health. The study of these new proteins will help develop therapies for mineral loss disorders (inherited and tumor-acquired), renal osteodystrophy, renal transplantation, ectopic arterial-calcification, renal calcification and osteoporosis.
|Norden, A G W; Laing, R J C; Rowe, P et al. (2014) Oncogenic osteomalacia, raised FGF-23, and renal Fanconi syndrome. QJM 107:139-41|
|Zelenchuk, Lesya V; Hedge, Anne-Marie; Rowe, Peter S N (2014) PHEX mimetic (SPR4-peptide) corrects and improves HYP and wild type mice energy-metabolism. PLoS One 9:e97326|
|Salmon, B; Bardet, C; Coyac, B R et al. (2014) Abnormal osteopontin and matrix extracellular phosphoglycoprotein localization, and odontoblast differentiation, in X-linked hypophosphatemic teeth. Connect Tissue Res 55 Suppl 1:79-82|
|Salmon, Benjamin; Bardet, Claire; Khaddam, Mayssam et al. (2013) MEPE-derived ASARM peptide inhibits odontogenic differentiation of dental pulp stem cells and impairs mineralization in tooth models of X-linked hypophosphatemia. PLoS One 8:e56749|
|Opsahl Vital, S; Gaucher, C; Bardet, C et al. (2012) Tooth dentin defects reflect genetic disorders affecting bone mineralization. Bone 50:989-97|
|Rowe, Peter S N (2012) Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway. Crit Rev Eukaryot Gene Expr 22:61-86|
|David, Valentin; Martin, Aline; Hedge, Anne-Marie et al. (2011) ASARM peptides: PHEX-dependent and -independent regulation of serum phosphate. Am J Physiol Renal Physiol 300:F783-91|
|Atkins, Gerald J; Rowe, Peter S; Lim, Hui P et al. (2011) Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. J Bone Miner Res 26:1425-36|
|Boukpessi, Tchilalo; Gaucher, Celine; Leger, Thibaut et al. (2010) Abnormal presence of the matrix extracellular phosphoglycoprotein-derived acidic serine- and aspartate-rich motif peptide in human hypophosphatemic dentin. Am J Pathol 177:803-12|
|Boskey, Adele L; Chiang, Phyllis; Fermanis, Alexis et al. (2010) MEPE's diverse effects on mineralization. Calcif Tissue Int 86:42-6|
Showing the most recent 10 out of 18 publications