MicroRNA‐155 inhibition up‐regulates LEPR to inhibit osteoclast activation and bone resorption via activation of AMPK in alendronate‐treated osteoporotic mice

Abstract

Osteoporosis is characterized by a progressive increase in bone fragility, leading to low bone mass and structural deterioration of bone tissue. is highly expressed in osteoporosis. Thus, the current study aimed to investigate the effect of miR-155 on the inhibition of osteoclast activation and bone resorption by targeting leptin receptor (LEPR) through the adenosine monophosphate activated protein kinase (AMPK) pathway in alendronate-treated osteoporotic mice. An osteoporosis mouse model was established to examine the bone tension and bone density and the expression of miR-155 in osteoclasts. Binding sites between miR-155 and LEPR were verified. Osteoclasts in the treatment group were transfected with different mimic, inhibitor, vector, or siRNA for subsequent experiments. The expression of miR-155, LEPR, AMPK, p-AMPK, RANKL, OPG, M-CSF, RANK, TRAP, Bax, Bcl-2, and the contents of TNF-α and IL-1β were all examined. The proliferation and bone resorption of osteoclasts were also detected. Mice with osteoporosis exhibited decreased bone density and bone tension, along with elevated expression of miR-155. LEPR was verified as a target gene of miR-155. Down-regulated miR-155 was found to increase the expression of LEPR, AMPK, p-AMPK, OPG, Bax, decrease expression of TNF-α, IL-1β, RANKL, M-CSF, RANK, TRAP, Bcl-2, inhibit the cell proliferation and bone resorption of osteoclasts. Taken together, decreased miR-155 up-regulated LEPR via activation of AMPK, which ultimately repressed osteoclast activation and bone resorption of osteoclasts in alendronatetreated osteoporotic mice. K E Y W O R D S AMPK pathway, bone resorption, LEPR, microRNA-155, osteoclast, osteoporosis, proliferationAbbreviations: AMPK, adenosine monophosphate activated protein kinase; ANOVA, analysis of variance; ECL, electrochemiluminescence; ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine serum; LEPR, leptin receptor; M-CSF, macrophage colony stimulating factor; miR-155, microRNA-155; NC, negative control; OD, optical density; PCV, pack cell volume; RT-qPCR, reverse transcription quantitative polymerase chain reaction; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; TBST, tris buffered saline tween; TRAP, tartaric acid phosphatase; TRAP, tartrate resistant acid phosphatase; WT, wild type.

miRNA-7062-5p Promoting Bone Resorption After Bone Metastasis of Colorectal Cancer Through Inhibiting GPR65

“…Moreover, miR-7062-5p also downregulated activation of AMPKα, which can be rescued by overexpression of GPR65; thus, we demonstrated that AMPK is downstream of GPR65, and both of them can be regulated by miR-7062-5p. Numerous evidence demonstrated that activation of AMPK negatively regulated osteoclastogenesis (Dong et al, 2018;Tong et al, 2018;Mao et al, 2019). The AMPK pathway can inhibit the activation of the JNK pathway (Lin et al, 2016;Chen S. et al, 2018, which is a key way of stimulating osteoclast formation.…”

Association of MIR17HG and MIR155HG gene variants with steroid-induced osteonecrosis of the femoral head in the population of northern China

“…According to the literature, miR-155 is involved in the regulation of OCs. In osteoporotic mice, miR-155 inhibited OC activation by targeting the leptin receptor ( LEPR) via the AMPK pathway [ 12 ]. MiR-155 can target proto-oncogene SPI1 , microsomia-related transcription factor, and cytokine signal transduction inhibitor protein 1 to inhibit macrophage activation and OC differentiation, thus inhibiting the process of bone resorption [ 16 ].…”

Association of MIR17HG and MIR155HG gene variants with steroid-induced osteonecrosis of the femoral head in the population of northern China

“…According to the literature, miR-155 is involved in the regulation of OCs. In osteoporotic mice, miR-155 inhibited OC activation by targeting the leptin receptor (LEPR) via the AMPK pathway (Mao et al, 2019). MiR-155 can target proto-oncogene SPI1, microsomia-related transcription factor and cytokine signal transduction inhibitor protein 1 to inhibit macrophage activation and OC differentiation, thus inhibiting the process of bone resorption (Song et al, 2019).…”