microRNA Signature in Adult Patients with Hypophosphatasia

Introduction Hypophosphatasia (HPP) is a rare genetic disorder, characterized by hypomineralization, recurrent fractures, musculoskeletal pain and extra-skeletal manifestations. The serological hallmark is low TNSALP (tissue non-specific alkaline phosphatase) activity and accumulation of natural substrates, such as PLP (Pyridoxalphosphate). Data on microRNAs (miRNAs) are lacking.

Methods Circulating miRNAs, PLP and established bone turnover markers were analyzed in a cohort of adult HPP patients and healthy age- and sex-matched controls (CTRLs) in a cross-sectional design. RNA extraction from 200 µl serum was performed using the miRNeasy Mini Kit (Qiagen, Germany) and a validated small RNA-sequencing workflow (TAmiRNA). Bone mineral density (BMD) was carried out by dual energy X-ray absorptiometry (DXA).

Results Serum of 24 adult HPP patients and 24 CTRLs (47.9±14.2 vs.45.9±8.8 years, p=0.980) were analyzed. Alkaline phosphatase levels (ALP) were significantly lower in HPP than CTRLs (U/L;23±11 vs. 54±28, <0.0001). PLP-levels were above the reference range in 67% of patients (µg/L;36.3±98.2). Established bone turnover markers and BMD were in normal range (T-score femoral neck: -0.5±1.2, T-score lumbar spine L1-4: 0.1±1.7). In total, 72 miRNAs were differentially regulated in HPP vs. CTRLs (43 up- and 29 down-regulated, p-adj<0.05 for all). Seven of these miRNAs were Osteo-miRs (miR-19b-3p, miR-141-3p, miR-451a, miR-23a-3p, miR-144-5p, miR-143-3p, miR-375-3p). Patients reporting muskuloskeletal pain showed an upregulation of miR-26b-5p (p=0.05), a miRNA associated with osteogenesis, and patients with dentification disorder showed downregulation on miR-23a-3p (p=0.04) and miR-590-3p (p=0.05). Further, elevated PLP levels were associated with a down-regulation of miR-1-3p (p=0.02) and miR-29a-3p (p=0.03), both myo-miRs (muscle).

Discussion Adult HPP patients show a distinctive miRNA-signature compared to healthy population and further associations to clinical manifestations. Differently regulated miRNAs have a known association to the musculoskeletal system including osteogenic differentiation and/or proliferation, as well as reduced muscle mass, strength and function.

Keywords hypophosphatasia, miRNA, bone,muscle

Korrespondenzadresse Judith Haschka, Ludwig Boltzmann Institut für Osteologie, Hanusch Krankenhaus, 1. Medizinische Abteilung, Heinrich-Collin-Straße 30, 1140 Wien, Österreich, E-Mail: [e-mail]

Publication History

Article published online:
16 June 2023