RRC ID 43939
Author Staines KA, Mackenzie NC, Clarkin CE, Zelenchuk L, Rowe PS, MacRae VE, Farquharson C.
Title MEPE is a novel regulator of growth plate cartilage mineralization.
Journal Bone
Abstract Matrix extracellular phosphoglycoprotein (MEPE) belongs to the SIBLING protein family which play key roles in biomineralization. Although the growth plates of MEPE-overexpressing mice display severe morphological disruption, the expression and function of MEPE in growth plate matrix mineralization remains largely undefined. Here we show MEPE and its cleavage product, the acidic serine aspartate-rich MEPE-associated motif (ASARM) peptide, to be localised to the hypertrophic zone of the growth plate. We also demonstrate that the phosphorylated (p)ASARM peptide inhibits ATDC5 chondrocyte matrix mineralization. Stable MEPE-overexpressing ATDC5 cells also had significantly reduced matrix mineralization in comparison to the control cells. Interestingly, we show that the addition of the non-phosphorylated (np)ASARM peptide promoted mineralization in the ATDC5 cells. The peptides and the overexpression of MEPE did not affect the differentiation of the ATDC5 cells. For a more physiologically relevant model, we utilized the metatarsal organ culture model. We show the pASARM peptide to inhibit mineralization at two stages of development, as shown by histological and μCT analysis. Like in the ATDC5 cells, the peptides did not affect the differentiation of the metatarsals indicating that the effects seen on mineralization are direct, as is additionally confirmed by no change in alkaline phosphatase activity or mRNA expression. In the metatarsal organ cultures, the pASARM peptide also reduced endothelial cell markers and vascular endothelial growth factor mRNA expression. Taken together these results show MEPE to be an important regulator of growth plate chondrocyte matrix mineralization through its cleavage to an ASARM peptide.
Volume 51(3)
Pages 418-30
Published 2012-9-1
DOI 10.1016/j.bone.2012.06.022
PII S8756-3282(12)00949-0
PMID 22766095
PMC PMC3427007
MeSH Alkaline Phosphatase / metabolism Amino Acid Sequence Animals Biomarkers / metabolism Bone Matrix / drug effects Bone Matrix / metabolism Calcification, Physiologic* / drug effects Cartilage / cytology Cartilage / drug effects Cartilage / metabolism* Extracellular Matrix Proteins / genetics Extracellular Matrix Proteins / metabolism* Gene Expression Regulation / drug effects Glycoproteins / genetics Glycoproteins / metabolism* Growth Plate / cytology Growth Plate / drug effects Growth Plate / metabolism* Metatarsal Bones / embryology Metatarsal Bones / metabolism Mice Mice, Inbred C57BL Molecular Sequence Data Peptides / chemistry Peptides / metabolism Peptides / pharmacology Phosphoproteins / genetics Phosphoproteins / metabolism* Phosphorylation / drug effects RNA, Messenger / genetics RNA, Messenger / metabolism Tibia / cytology Tibia / drug effects Tibia / metabolism
IF 4.36
Times Cited 31
WOS Category ENDOCRINOLOGY & METABOLISM
Resource
Human and Animal Cells