Dataset Information

Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif.

ABSTRACT: Mice with null mutations in matrix extracellular phosphoglycoprotein (MEPE) have increased bone mass, increased trabecular density and abnormal cancellous bone (MN-mice). These defects worsen with age and MEPE overexpression induces opposite effects. Also, genome wide association studies show that MEPE plays a major role in bone mass. We hypothesized that the conserved C-terminal MEPE ASARM-motif is chiefly responsible for regulating bone mass and trabecular structure.To test our theory we overexpressed C-terminal ASARM-peptide in MN-mice using the Col1?1 promoter (MNAt-mice). We then compared the bone and renal phenotypes of the MNAt-mouse with the MN-mouse and the X-linked hypophosphatemic rickets mouse (HYP). The HYP mouse overexpresses ASARM-peptides and is defective for the PHEX gene.The MN-mouse developed increased bone mass, bone strength and trabecular abnormalities that worsened markedly with age. Defects in bone formation were chiefly responsible with suppressed sclerostin and increased active ?-catenin. Increased uric acid levels also suggested that abnormalities in purine-metabolism and a reduced fractional excretion of uric acid signaled additional renal transport changes. The MN mouse developed a worsening hyperphosphatemia and reduced FGF23 with age. An increase in the fractional excretion of phosphate (FEP) despite the hyperphosphatemia confirms an imbalance in kidney-intestinal phosphate regulation. Also, the MN mice showed an increased creatinine clearance suggesting hyperfiltration. A reversal of the MN bone-renal phenotype changes occurred with the MNAt mice including the apparent hyperfiltration. The MNAt mice also developed localized hypomineralization, hypophosphatemia and increased FGF23.The C-terminal ASARM-motif plays a major role in regulating bone-mass and cancellous structure as mice age. In healthy mice, the processing and release of free ASARM-peptide are chiefly responsible for preserving normal bone and renal function. Free ASARM-peptide also affects renal mineral phosphate handling by influencing FGF23 expression. These findings have implications for understanding age-dependent osteoporosis, unraveling drug-targets and developing treatments.

SUBMITTER: Zelenchuk LV

PROVIDER: S-EPMC4501877 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif.

Zelenchuk Lesya V LV Hedge Anne-Marie AM Rowe Peter S N PS

Bone 20150604

<h4>Context</h4>Mice with null mutations in matrix extracellular phosphoglycoprotein (MEPE) have increased bone mass, increased trabecular density and abnormal cancellous bone (MN-mice). These defects worsen with age and MEPE overexpression induces opposite effects. Also, genome wide association studies show that MEPE plays a major role in bone mass. We hypothesized that the conserved C-terminal MEPE ASARM-motif is chiefly responsible for regulating bone mass and trabecular structure.<h4>Design< ...[more]

PMID: 26051469

Similar Datasets

Project description:Background: Age-dependent renal impairment contributes to renal dysfunction in both the general population and young and middle-aged patients with renal diseases. Pathological changes in age-dependent renal impairment include glomerulosclerosis and tubulointerstitial fibrosis. The molecules involved in age-dependent renal impairment are not fully elucidated. MicroRNA (miRNA) species were reported to modulate various renal diseases, but the miRNA species involved in age-dependent renal impairment are unclear. Here, we investigated miRNAs in age-dependent renal impairment, and we evaluated their potential as biomarkers and therapeutic targets. Methods: We conducted an initial microarray profiling analysis to screen miRNAs whose expression levels changed in kidneys of senescence-accelerated resistant (SAMR1)-10-week-old (wk) mice and SAMR1-50wk mice and senescence-accelerated prone (SAMP1)-10wk mice and SAMP1-50wk mice. We then evaluated the expressions of differentially expressed miRNAs in serum from 13 older patients (>65 years old) with age-dependent renal impairment (estimated glomerular filtration ratio <60 mL/min/1.73 m2) by a quantitative real-time polymerase chain reaction (qRT-PCR) and compared the expressions with those of age-matched subjects with normal renal function. We also administered miRNA mimics or inhibitors (5 nmol) with a nonviral vector (polyethylenimine nanoparticles: PEI-NPs) to SAMP1-20wk mice to investigate the therapeutic effects. Results: The qRT-PCR revealed a specific miRNA (miRNA-503-5p) whose level was significantly changed in SAMP1-50wk mouse kidneys in comparison to the controls. The expression level of miRNA-503-5p was upregulated in the serum of the 13 patients with age-dependent renal impairment compared to the age-matched subjects with normal renal function. The administration of a miRNA-503-5p-inhibitor with PEI-NPs decreased the miRNA-503-5p expression levels, resulting in the inhibition of renal fibrosis in mice via an inhibition of a pro-fibrotic signaling pathway and a suppression of glomerulosclerosis in mice by inhibiting intrinsic signaling pathways. Conclusion: miRNA-503-5p may represent a biomarker for age-dependent renal impairment, and the inhibition of miRNA-503-5p had no effect on age-dependent renal impairment. However, the inhibition of miRNA-503-5p had therapeutic effects on renal fibrosis and glomerulosclerosis.

Dataset Information

Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif.

Publications

Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets