Abstract
Osteoporosis is a complex multifactorial disorder linked to various risk factors and medical conditions. Bone marrow-derived mesenchymal stem cell (BMSC) dysfunction potentially plays a critical role in osteoporosis pathogenesis. Herein, the study identified that miR-4739 was upregulated in BMSC cultures harvested from osteoporotic subjects. BMSCs were isolated from normal and osteoporotic bone marrow tissues and identified for their osteogenic differentiation potential. In osteoporotic BMSCs, miR-4739 overexpression significantly inhibited cell viability, osteoblast differentiation, mineralized nodule formation, and heterotopic bone formation, whereas miR-4739 inhibition exerted opposite effects. Through direct binding, miR-4739 inhibited distal-less homeobox 3 (DLX3) expression. In osteoporotic BMSCs, DLX3 knockdown also inhibited BMSC viability and osteogenic differentiation. Moreover, DLX3 knockdown partially attenuated the effects of miR-4739 inhibition upon BMSCs. Altogether, the miR-4739/DLX3 axis modulates the capacity of BMSCs to differentiate into osteoblasts, which potentially plays a role in osteoporosis pathogenesis. The in vivo and clinical functions of the miR-4739/DLX3 axis require further investigation.
Highlights
Osteoporosis is a complex multifactorial disorder that is related to various risk factors and medical conditions
To identify miRNAs that potentially regulate the osteogenic differentiation of osteoporotic Bone marrow-derived mesenchymal stem cell (BMSC), differentially expressed miRNAs were analyzed using online microarray chip data from Gene Expression Omnibus (GEO) (Figure 1A)
According to GSE74209 containing miRNAs differentially expressed in postmenopausal women experiencing hip arthroplasty due to either osteoporotic fracture or osteoarthritis without osteoporosis (Figure 1C, Figure S1A and Table S2) and GSE93883 containing miRNAs differentially expressed in non-osteoporotic patients and patients with osteoporosis in the presence or absence of vertebral fractures (Figure 1D, Figure S1B and Table S2), 3 upregulated miRNAs were overlapped in two datasets (Figures 1A, C, D)
Summary
Osteoporosis is a complex multifactorial disorder that is related to various risk factors and medical conditions. Bone regeneration through BMSCs infusion could miR-4739/DLX3 Modulates Osteoporosis Progression trigger osteogenesis, thereby providing a potential therapeutic strategy for primary osteoporosis [7]. Several studies indicated the potential roles of miRNAs in osteoporosis pathogenesis, affecting BMSC osteogenic differentiation [13,14,15,16]. Li et al [13] indicated that miR-188 is an important regulator of the age-associated switch between osteoblast and adipocyte differentiation of BMSCs, representing an underlying therapeutic target for age-associated bone loss. Wang and colleagues analyzed RNA-seq and miRNAmicroarray data for differentially expressed between the ovariectomized (OVX) mice and controls, and 22 miRNAs were identified [17]. Considering that miRNAs exert regulatory roles in target gene expression, identifying more miRNA/mRNA axes modulating BMSC osteogenic differentiation could potentially provide potential agents for osteoporosis treatment
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