Unique, Gender-Dependent Serum microRNA Profile inPLS3 Gene-Related Osteoporosis

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Mäkitie , R E , Hackl , M , Weigl , M , Frischer , A , Kämpe , A , Costantini , A , Grillari , J & Mäkitie , O 2020 , ' Unique, Gender-Dependent Serum microRNA Profile inPLS3 Gene-Related Osteoporosis ' , Journal of Bone and Mineral Research , vol. 35 , no. 10 , pp. 1962-1973 . https://doi.org/10.1002/jbmr.4097

Title: Unique, Gender-Dependent Serum microRNA Profile inPLS3 Gene-Related Osteoporosis
Author: Mäkitie, Riikka E.; Hackl, Matthias; Weigl, Moritz; Frischer, Amelie; Kämpe, Anders; Costantini, Alice; Grillari, Johannes; Mäkitie, Outi
Contributor: University of Helsinki, HUS Internal Medicine and Rehabilitation
University of Helsinki, HUS Children and Adolescents
Date: 2020-10
Language: eng
Number of pages: 12
Belongs to series: Journal of Bone and Mineral Research
ISSN: 0884-0431
URI: http://hdl.handle.net/10138/320787
Abstract: Plastin 3 (PLS3), encoded byPLS3, is a newly recognized regulator of bone metabolism, and mutations in the encoding gene result in severe childhood-onset osteoporosis. Because it is an X chromosomal gene,PLS3mutation-positive males are typically more severely affected whereas females portray normal to increased skeletal fragility. Despite the severe skeletal pathology, conventional metabolic bone markers tend to be normal and are thus insufficient for diagnosing or monitoring patients. Our study aimed to explore serum microRNA (miRNA) concentrations in subjects with defective PLS3 function to identify novel markers that could differentiate subjects according to mutation status and give insight into the molecular mechanisms by which PLS3 regulates skeletal health. We analyzed fasting serum samples for a custom-designed panel comprising 192 miRNAs in 15 mutation-positive (five males, age range 8-76 years, median 41 years) and 14 mutation-negative (six males, age range 8-69 years, median 40 years) subjects from four Finnish families with differentPLS3mutations. We identified a unique miRNA expression profile in the mutation-positive subjects with seven significantly upregulated or downregulated miRNAs (miR-93-3p, miR-532-3p, miR-133a-3p, miR-301b-3p, miR-181c-5p, miR-203a-3p, and miR-590-3p;pvalues, range .004-.044). Surprisingly, gender subgroup analysis revealed the difference to be even more distinct in female mutation-positive subjects (congruentpvalues, range .007-.086) than in males (pvalues, range .127-.843) in comparison to corresponding mutation-negative subjects. Although the seven identified miRNAs have all been linked to bone metabolism and two of them (miR-181c-5p and miR-203a-3p) have bioinformatically predicted targets in thePLS33 ' untranslated region (3 '-UTR), none have previously been reported to associate with PLS3. Our results indicate thatPLS3mutations are reflected in altered serum miRNA levels and suggest there is crosstalk between PLS3 and these miRNAs in bone metabolism. These provide new understanding of the pathomechanisms by which mutations inPLS3lead to skeletal disease and may provide novel avenues for exploring miRNAs as biomarkers in PLS3 osteoporosis or as target molecules in future therapeutic applications. (c) 2020 The Authors.Journal of Bone and Mineral Researchpublished by American Society for Bone and Mineral Research.
Subject: BIOCHEMICAL MARKERS OF BONE TURNOVER
CELL
TISSUE SIGNALING - PARACRINE PATHWAYS
GENETIC RESEARCH
OSTEOGENESIS IMPERFECTA
OSTEOPOROSIS
OSTEOGENIC DIFFERENTIATION
MICRORNA PROFILE
STEM-CELLS
BONE
DISEASE
CANCER
PROGRESSION
SIGNATURES
MUTATIONS
MIR-203
3121 General medicine, internal medicine and other clinical medicine
1182 Biochemistry, cell and molecular biology
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