MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM
- PMID: 18597632
- DOI: 10.1359/jbmr.080601
MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM
Abstract
Hyp mice having an inactivating mutation of the phosphate-regulating gene with homologies to endopeptidases on the X-chromosome (Phex) gene have bones with increased matrix extracellular phosphoglycoprotein (MEPE). An acidic, serine- and aspartic acid-rich motif (ASARM) is located in the C terminus of MEPE and other mineralized tissue matrix proteins. We studied the effects of ASARM peptides on mineralization and how PHEX and MEPE interactions contribute to X-linked hypophosphatemia (XLH). ASARM immunoreactivity was observed in the osteoid of wildtype bone and in the increased osteoid of Hyp mice. In wildtype bone, PHEX immunostaining was found particularly in osteoid osteocytes and their surrounding matrix. Treatment of MC3T3-E1 osteoblasts with triphosphorylated (3 phosphoserines) ASARM peptide (pASARM) caused a dose-dependent inhibition of mineralization. pASARM did not affect collagen deposition or osteoblast differentiation, suggesting that pASARM inhibits mineralization by direct binding to hydroxyapatite crystals. Binding of pASARM to mineralization foci in pASARM-treated cultures and to synthetic hydroxyapatite crystals was confirmed by colloidal-gold immunolabeling. Nonphosphorylated ASARM peptide showed little or no binding to hydroxyapatite and did not inhibit mineralization, showing the importance of ASARM phosphorylation in regulating mineralization. PHEX rescued the inhibition of osteoblast culture mineralization by pASARM, and mass spectrometry of cleaved peptides obtained after pASARM-PHEX incubations identified pASARM as a substrate for PHEX. These results, showing that pASARM inhibits mineralization by binding to hydroxyapatite and that this inhibitor can be cleaved by PHEX, provide a mechanism explaining how loss of PHEX activity can lead to extracellular matrix accumulation of ASARM resulting in the osteomalacia of XLH.
Similar articles
-
Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage.J Bone Miner Res. 2010 Apr;25(4):695-705. doi: 10.1359/jbmr.090832. J Bone Miner Res. 2010. PMID: 19775205
-
Active sites of human MEPE-ASARM regulating bone matrix mineralization.Mol Cell Endocrinol. 2020 Nov 1;517:110931. doi: 10.1016/j.mce.2020.110931. Epub 2020 Jul 24. Mol Cell Endocrinol. 2020. PMID: 32712387
-
Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP.Endocrinology. 2008 Apr;149(4):1757-72. doi: 10.1210/en.2007-1205. Epub 2007 Dec 27. Endocrinology. 2008. PMID: 18162525 Free PMC article.
-
FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization.Am J Physiol Endocrinol Metab. 2003 Jul;285(1):E1-9. doi: 10.1152/ajpendo.00016.2003. Am J Physiol Endocrinol Metab. 2003. PMID: 12791601 Review.
-
Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway.Crit Rev Eukaryot Gene Expr. 2012;22(1):61-86. doi: 10.1615/critreveukargeneexpr.v22.i1.50. Crit Rev Eukaryot Gene Expr. 2012. PMID: 22339660 Free PMC article. Review.
Cited by
-
MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway.Front Endocrinol (Lausanne). 2022 Sep 29;13:977347. doi: 10.3389/fendo.2022.977347. eCollection 2022. Front Endocrinol (Lausanne). 2022. PMID: 36267566 Free PMC article.
-
FGF23 production by osteocytes.Pediatr Nephrol. 2013 Apr;28(4):563-8. doi: 10.1007/s00467-012-2309-3. Epub 2012 Sep 16. Pediatr Nephrol. 2013. PMID: 22983423 Free PMC article. Review.
-
Collagen osteoid-like model allows kinetic gene expression studies of non-collagenous proteins in relation with mineral development to understand bone biomineralization.PLoS One. 2013;8(2):e57344. doi: 10.1371/journal.pone.0057344. Epub 2013 Feb 27. PLoS One. 2013. PMID: 23460841 Free PMC article.
-
The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment.J Bone Miner Res. 2011 Feb;26(2):331-40. doi: 10.1002/jbmr.226. J Bone Miner Res. 2011. PMID: 20734454 Free PMC article.
-
Contributions of increased osteopontin and hypophosphatemia to dentoalveolar defects in osteomalacic Hyp mice.Bone. 2023 Nov;176:116886. doi: 10.1016/j.bone.2023.116886. Epub 2023 Aug 25. Bone. 2023. PMID: 37634682 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases