Silencing of miR-138-5p sensitizes bone anabolic action to mechanical stimuli

Abstract

Emerging evidence is revealing that microRNAs (miRNAs) play essential roles in mechanosensing for regulating osteogenesis. However, no mechanoresponsive miRNAs have been identified in human bone specimens. Methods: Bedridden and aged patients, hindlimb unloaded and aged mice, and Random Positioning Machine and primary aged osteoblasts were adopted to simulate mechanical unloading conditions at the human, animal and cellular levels, respectively. Treadmill exercise and Flexcell cyclic mechanical stretching were used to simulate mechanical loading in vivo and in vitro , respectively. Results: Here, we found increased miR-138-5p levels with a lower degree of bone formation in bone specimens from bedridden and aged patients. Loss- and gain-of-function studies showed that miR-138-5p directly targeted microtubule actin crosslinking factor 1 (MACF1) to inhibit osteoblast differentiation under different mechanical conditions. Regarding translational medicine, bone-targeted inhibition of miR-138-5p attenuated the decrease in the mechanical bone anabolic response in hindlimb unloaded mice. Moreover, bone-targeted inhibition of miR-138-5p sensitized the bone anabolic response to mechanical loading in both miR-138-5p transgenic mice and aged mice to promote bone formation. Conclusion: These data suggest that miR-138-5p as a mechanoresponsive miRNA accounts for the mechanosensitivity of the bone anabolic response and that inhibition of miR-138-5p in osteoblasts may be a novel bone anabolic sensitization strategy for ameliorating disuse or senile osteoporosis.

Acacetin Prevents Bone Loss by Disrupting Osteoclast Formation and Promoting Type H Vessel Formation in Ovariectomy-Induced Osteoporosis

“…The number of positively stained cells in the field of distal femoral metaphysis was calculated and normalized to the number per square millimetre (N·mm −2 ) of bone marrow area in the trabecular bone. For immunohistochemistry analyses ( Zhihao Chen et al, 2020 ), sections were processed for antigen retrieval for 15 min and blocked in 3% BSA for 30 min. The sections were then incubated overnight with primary antibody against CTSK (1:100) at 4°C, and incubated with HRP-conjugated IgG (1:400) for 50 min after three washes with PBS.…”

Analysis of CircRNA Expression Profile of Pathological Bone Formation in Ankylosing Spondylitis

“…The results showed that these differentially expressed circRNAs have not been reported in ankylosing spondylitis, but the research of miRNA in ankylosing spondylitis and orthopedic related diseases is relatively mature. We found that has-miR-34a, has-miR-503-5p and has-miR-138-5p were associated with mechanical reactive osteogenesis, and we found a competitive combination of circRNA in our circRNA-miRNAmRNA network diagram [13][14][15], so we inferred that differentially up and down regulated circRNAs were associated with pathological osteogenesis and inflammation.…”

Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss

“…It is known that miRNAs are present in cytoplasm in the form of RISC with a core AGO2 component. Emerging research suggests that endogenous miRNAs could bind directly to promoters to regulate gene expression in response to different survival conditions 34 - 36 . For example, miR-320 localized to the nuclei under hyperglycemic conditions 37 and miR‑210‑3p was highly expressed in nuclei after hypoxic stimulus 38 .…”