MiRNA-133a is involved in the regulation of postmenopausal osteoporosis through promoting osteoclast differentiation

Abstract

The important role of miR-133a in the progress and development of postmenopausal osteoporosis has been reported, however, the underlying mechanism is not clear yet. In this study, qRT-PCR analysis was performed to assess miR-133 expression in serum isolated from postmenopausal osteoporosis patients (PMOP) and healthy controls. Bone mineral density (BMD) was measured at the lumbar spine by dual-energy X-ray absorptiometry (DXA). The results showed that miR-133a was significantly upregulated and negatively correlated with lumbar spine BMD in serum of postmenopausal osteoporotic women. The miR-133a mimic, miR-133a inhibitor, and the corresponding controls were transfected into RAW264.7 and THP-1 cells, respectively. TRAP-positive cells were counted and the protein expression of NFATc1, c-Fos and TRAP were detected by western blot analysis. We found that MiR-133a was upregulated during osteoclastogenesis, and overexpression of miR-133a promoted RANKL-induced differentiation of RAW264.7 and THP-1 cells into osteoclasts, whereas miR-133a knockdown showed the reversed results. In in vivo experiment, rats were bilaterally ovariectomized (OVX) and injected with antagomiR-133a or antagoNC, and were sacrificed for collecting serum and lumbar spine for ELISA, micro-computed Tomography (CT) and bone histomorphology analysis, respectively. It was found that, in OVX rats, miR-133a knockdown altered the levels of osteoclastogenesis-related factors in serum and increased lumbar spine BMD and changed bone histomorphology. Collectively, miRNA-133a is involved in the regulation of postmenopausal osteoporosis through promoting osteoclast differentiation.

MicroRNA and Human Bone Health

“…In the TPTD treatment group, miR‐133a and miR‐33 levels were significantly decreased after 3 to 12 months of treatment. As shown in other human studies, miR‐133a could promote osteoclast differentiation, and its level was correlated with low BMD in postmenopausal women . It was also shown that miR‐133a could hamper bone formation by targeting RUNX2 .…”

“…Using bioinformatics analysis, osteoblast‐related genes, such as CXCL11, CXCR3, and SLC39A1, were found to be potential downstream targets. Two subsequent studies in Chinese postmenopausal women also reported increased miR‐133a levels in serum and plasma of low BMD group …”

“…Liz and colleagues provided evidence that miR‐133a could contribute to RANKL‐induced osteoclast differentiation . By overexpressing miR‐133a in R264.7 and THP‐1 cells, expressions of osteoclastogenesis markers (NFATc1, c‐Fos, and TRAP) were induced, whereas in miR‐133a knockdown, expressions of these markers were suppressed.…”

microRNA‐Mediated Regulation of Bone Remodeling: A Brief Review

“…The study has provided experimental and clinical evidence to delineate the role of miRNAs in regulating osteolytic bone metastasis. It is interesting to note that miR‐133a was found to inhibit osteoclast differentiation and resorption activity in vitro, in contrast to the aforementioned positive regulatory role of miR‐133a in osteoclasts, which may attribute to the different disease mechanism between osteoporosis and cancer bone metastasis. In addition, our laboratory has identified that miR‐214‐3p was significantly upregulated in bone specimens from breast cancer patients with osteolytic bone metastasis .…”

“…Li and colleagues detected the upregulated miR‐133a in serum isolated from postmenopausal osteoporosis patients, which was negatively correlated with the patients’ lumbar bone mineral density (BMD). They demonstrated that miR‐133a knockdown could inhibit the RANKL‐induced osteoclastogenesis in vitro and alleviated the bone loss in ovariectomized rats in vivo.…”