MiR-23b-3p promotes postmenopausal osteoporosis by targeting MRC2 and regulating the Wnt/β-catenin signaling pathway.

Postmenopausal osteoporosis (PMOP) is one of the most common metabolic bone diseases in postmenopausal women. Increasing evidence has indicated that microRNAs (miRNAs) play vital regulatory roles during osteoporosis progression. This study aimed to investigate the potential function of miR-23b-3p in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs). PMOP was induced in mice by bilateral ovariectomy. X-ray absorptiometry was applied to detect BMD and BMC in PMOP mice. Luciferase reporter assay and RIP assay were utilized to investigate the relationship between miR-23b-3p and MRC2. We found the upregulation of miR-23b-3p in bone tissues of PMOP mice. Silencing of miR-23b-3p relieved PMOP in mice. Moreover, miR-23b-3p knockdown facilitated the osteogenic differentiation of hMSCs by increasing the expression of Runx2, OCN, Osterix and promoting ALP activity. Mechanistically, MRC2 is a downstream target gene of miR-23b-3p. MRC2 knockdown significantly rescued the promoting effect of lenti-miR-23b-3p inhibitor on osteogenic differentiation of hMSCs. Furthermore, miR-23b-3p targeted MRC2 to inhibit the Wnt/β-catenin pathway during the osteogenic differentiation of hMSCs. In summary, inhibition of miR-23b-3p alleviates PMOP by targeting MRC2 to inhibit the Wnt/β-catenin signaling, which may provide a novel molecular insight for osteoporosis therapy.

Li R ，Ruan Q ，Yin F ，Zhao K ... -  《-》

Mir-381-3p aggravates ovariectomy-induced osteoporosis by inhibiting osteogenic differentiation through targeting KLF5/Wnt/β-catenin signaling pathway.

Increasing evidence shows the pivotal significance of miRNAs in the pathogenesis of osteoporosis. miR-381-3p has been identified as an inhibitor of osteogenesis. This study explored the role and mechanism of miR-381-3p in postmenopausal osteoporosis (PMOP), the most common type of osteoporosis. Bilateral ovariectomy (OVX) rat model was established and miR-381-3p antagomir was administrated through the tail vein in vivo. The pathological changes in rats were assessed through the evaluation of serum bone turnover markers (BALP, PINP, and CTX-1), hematoxylin and eosin (H&E) staining, as well as the expression of osteoblast differentiation biomarkers. Moreover, isolated bone marrow mesenchymal stem cells from OVX-induced rats (OVX-BMMSCs) were utilized to explore the impact of miR-381-3p on osteoblast differentiation. In addition, the target gene and downstream pathway of miR-381-3p were further investigated both in vivo and in vitro. miR-381-3p expression was elevated, whereas KLF5 was suppressed in OVX rats. miR-381-3p antagomir decreased serum levels of bone turnover markers, improved trabecular separation, promoted osteoblast differentiation biomarker expression in OVX rats. ALP activity and mineralization were suppressed, and levels of osteoblast differentiation biomarkers were impeded after miR-381-3p overexpression during osteoblast differentiation of OVX-BMMSCs. While contrasting results were found after inhibition of miR-381-3p. miR-381-3p targets KLF5, negatively affecting its expression as well as its downstream Wnt/β-catenin pathway, both in vivo and in vitro. Silencing of KLF5 restored Wnt/β-catenin activation induced by miR-381-3p antagomir. miR-381-3p aggravates PMOP by inhibiting osteogenic differentiation through targeting KLF5/Wnt/β-catenin pathway. miR-381-3p appears to be a promising candidate for therapeutic intervention in PMOP.

Zhao Y ，Liu J ，Zhang Y ，Liang M ，Li R ，Song Y ，Wang Y ... -  《Journal of Orthopaedic Surgery and Research》

CircRNA hsa_circ_0006859 inhibits the osteogenic differentiation of BMSCs and aggravates osteoporosis by targeting miR-642b-5p/miR-483-3p and upregulating EFNA2/DOCK3.

Hsa_circ_0006859 has been found as a possible biomarker for postmenopausal osteoporosis (PMOP) with an effect on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but the underlying mechanism is unclear. Bioinformatics analysis was used to identify dysregulated RNAs involved in osteoporosis based on public datasets. Function assays were used to determine the functions of hsa_circ_0006859 on cell proliferation and osteogenic differentiation in vitro. It was found that hsa_circ_0006859 was upregulated in OVX mice-derived BMSCs, but lowly expressed during osteogenic differentiation. Overexpressing hsa_circ_0006859 inhibited the cell proliferation and osteogenesis of BMSCs and hFOB 1.19 cells, vice versa. Bilateral ovariectomy (OVX) was used to induce PMOP in mice. The interactions among circ_0006859, miR-642b-5p/miR-483-3p, and EFNA2/DOCK3 were determined using the RIP assay. Silencing circ_0006859 relieved PMOP in mice. Mechanistically, circ_0006859 bound to miR-642b-5p/miR-483-3p directly, while miR-642b-5p and miR-483-3p respectively targeted EFNA2 and DOCK3. Hsa_circ_0006859 downregulated the expression of miR-642b-5p/miR-483-3p to upregulate EFNA2/DOCK3. Additionally, miR-642b-5p/miR-483-3p targeted EFNA2/DOCK3 to inhibit BMSCs osteogenic differentiation and facilitate osteoporosis progression by inactivating the Wnt signaling. In conclusion, hsa_circ_0006859 is involved in PMOP by targeting miR-642b-5p/EFNA2 and miR-483-3p/DOCK3 axes to maintain the Wnt-signaling pathway, which may be a novel possible therapeutic targets and biomarkers for PMOP.

Yin P ，Xue Y 《-》

MiR-486-3p promotes osteogenic differentiation of BMSC by targeting CTNNBIP1 and activating the Wnt/β-catenin pathway.

Dysfunction in the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) leads to bone loss/osteoporosis. The catenin beta interacting protein 1 (CTNNBIP1) is an inhibitor of Wnt/β-catenin signaling, whose role in osteogenesis remains elusive. This study aimed to reveal the effects of miR-486-3p/CTNNBIP1 in osteogenesis. Bone marrow samples from healthy individuals and osteoporosis patients and mice with sham or ovariectomy (OVX) surgeries were collected. Levels of CTNNBIP1 and miR-486-3p were assessed. A dual-luciferase reporter assay was used to confirm the interactions between CTNNBIP1 and miR-486-3p. MiR-486-3p mimics/inhibitor or CTNNBIP1 overexpression lentiviruses were transfected to human BMSCs (hBMSCs) and an osteogenic assay was performed. Alizarin red S (ARS) and Alkaline phosphatase (ALP) intensity and expression of osteogenic genes Runx2, Alp, Cola1 and Bglap were measured. Key proteins in the Wnt/β-catenin pathway including active β-catenin, Bcl-2, and Cyclin D1 were assessed. CTNNBIP1 was upregulated while miR-486-3p was downregulated in osteoporosis patients and OVX mice. CTNNBIP1 was confirmed as a target of miR-486-3p. MiR-486-3p overexpression promoted, while miR-486-3p knockdown suppressed, osteogenic differentiation and Wnt/β-catenin signaling. Rescue experiments confirmed the negative effects of CTNNBIP1 overexpression on osteoblastic differentiation and that miR-486-3p mimics could reverse canonical Wnt signaling. This study demonstrated that miR-486-3p targets CTNNBIP1, thus activating the Wnt/β-catenin signaling pathway to promote osteogenesis of BMSCs.

Zhang Z ，Jiang W ，Hu M ，Gao R ，Zhou X ... -  《-》

LncRNA MEG3 inhibited osteogenic differentiation of bone marrow mesenchymal stem cells from postmenopausal osteoporosis by targeting miR-133a-3p.

Wang Q ，Li Y ，Zhang Y ，Ma L ，Lin L ，Meng J ，Jiang L ，Wang L ，Zhou P ，Zhang Y ... -  《-》