期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 35, 期 10, 页码 1962-1973出版社
WILEY
DOI: 10.1002/jbmr.4097
关键词
BIOCHEMICAL MARKERS OF BONE TURNOVER; CELL; TISSUE SIGNALING - PARACRINE PATHWAYS; GENETIC RESEARCH; OSTEOGENESIS IMPERFECTA; OSTEOPOROSIS
资金
- Sigrid Juselius Foundation
- Novo Nordisk Foundation
- Folkhalsan Research Foundation
- Academy of Finland
- Foundation for Pediatric Research
- Helsinki University Research Funds, Helsinki University
- Helsinki University Hospital through the Doctoral Programme in Clinical Research
- Orion Research Foundation
- Finnish Otorhinolaryngology-Head and Neck Surgery (ORL-HNS) Foundation
- Paivikki and Sakari Sohlberg Foundation
- Finnish-Norwegian Medical Foundation
- Jalmari and Rauha Ahokas Foundation
- Juhani Aho Foundation
- Swedish Research Council
- Swedish Childhood Cancer Foundation
- Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
- Stockholm County Council
- Karolinska Institutet
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.
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