Altered MicroRNA Profile in Osteoporosis Caused by Impaired WNT Signaling.

Altered MicroRNA Profile in Osteoporosis Caused by Impaired WNT Signaling.

J Clin Endocrinol Metab. 2018 Mar 01;:

Authors: Mäkitie RE, Hackl M, Niinimäki R, Kakko S, Grillari J, Mäkitie O

Abstract
Context: WNT signaling is fundamental to bone health and its aberrant activation leads to skeletal pathologies. A heterozygous missense mutation p.C218G in WNT1, a key WNT pathway ligand, leads to severe early-onset and progressive osteoporosis with multiple peripheral and spinal fractures. Despite the severe skeletal manifestations, conventional bone turnover markers are normal in mutation-positive patients.
Objective: This study sought to explore the circulating miRNA pattern in patients with impaired WNT signaling.
Design and Setting: A cross-sectional cohort study at a University Hospital.
Participants: Altogether 12 mutation-positive (median age 39 years, range 11-76 years) and 12 mutation-negative (35 years, range 9-59 years) subjects from two Finnish families with WNT1 osteoporosis due to the heterozygous p.C218G WNT1 mutation.
Methods and main outcome measure: Serum samples were screened for 192 miRNAs using qPCR. Findings were compared between WNT1 mutation-positive and mutation-negative subjects.
Results: The pattern of circulating miRNAs was significantly different in the mutation-positive subjects as compared with the mutation-negative subjects with 2 upregulated (miR-18a-3p, miR-223-3p) and 6 downregulated miRNAs (miR-22-3p, miR-31-5p, miR-34a-5p, miR-143-5p miR-423-5p, miR-423-3p). Three of these (miR-22-3p, miR-34a-5p, and miR-31-5p) are known inhibitors of WNT signaling: miR-22-3p and miR-34a-5p target WNT1 mRNA and miR-31-5p is predicted to bind to WNT1 3'UTR.
Conclusions: The circulating miRNA pattern reflects WNT1 mutation status. The findings suggest that the WNT1 mutation disrupts a feed-back regulation between these miRNAs and WNT1, providing new insights into the pathogenesis of WNT-related bone disorders. These miRNAs could offer future potential in diagnosis and treatment of osteoporosis.

PMID: 29506076 [PubMed - as supplied by publisher]

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