Focusing on OB-OC-MΦ Axis and miR-23a to Explore the Pathogenesis and Treatment Strategy of Osteoporosis

Abstract

Osteoporosis is a bone metabolic disorder characterized by decreased bone density and deteriorated microstructure, which increases the risk of fractures. The imbalance between bone formation and bone resorption results in the occurrence and progression of osteoporosis. Osteoblast-mediated bone formation, osteoclast-mediated bone resorption and macrophage-regulated inflammatory response play a central role in the process of bone remodeling, which together maintain the balance of the osteoblast-osteoclast-macrophage (OB-OC-MΦ) axis under physiological conditions. Bone formation and bone resorption disorders caused by the imbalance of OB-OC-MΦ axis contribute to osteoporosis. Many microRNAs are involved in the regulation of OB-OC-MΦ axis homeostasis, with microRNA-23a (miR-23a) being particularly crucial. MiR-23a is highly expressed in the pathological process of osteoporosis, which eventually leads to the occurrence and further progression of osteoporosis by inhibiting osteogenesis, promoting bone resorption and inflammatory polarization of macrophages. This review focuses on the role and mechanism of miR-23a in regulating the OB-OC-MΦ axis to provide new clinical strategies for the prevention and treatment of osteoporosis.

Keywords: cytokine; macrophage; miR-23a; osteoblast (OB); osteoclast (OC); osteoporosis.

Figure 1

OB-OC-MΦ axis in osteoporosis. Members of the OB-OC-MΦ axis maintain the axis’s equilibrium through intricate communication, which is mostly shown in appropriate levels of cytokines such as RANK, RNAKL, OPG, M-CSF, WNT5A, WNT16, and TNF-α. Endogenous or exogenous factors, such as evident inflammatory responses and aberrant hormone levels, might alter the levels of various cytokines, causing an imbalance of the OB-OC-MΦ axis and, ultimately, the occurrence and progression of osteoporosis. Brown arrows indicate the direction of cell differentiation, and small red arrows indicate abnormal changes in hormone or cytokine levels.

Figure 2

Regulation of miR-23a on OB-OC-MΦ axis. A high level of miR-23a impairs the balance of the OB-OC-MΦ axis, leading to the occurrence of osteoporosis. (A) Many kinds of cells can secrete exosomes or extracellular vesicles containing miR-23a. On the one hand, miR-23a can target Runx2, LPR5 and PGC1 to regulate osteoblast differentiation and maturation; On the other hand, it can target GSK3β and JAK1/STAT3 to regulate osteoclast differentiation. The regulation of miR-23a on osteoblasts can also indirectly affect the formation of osteoclasts. (B) In M1 macrophages, miR-23a specifically inhibits A20, eventually reducing its own expression and promoting the expression of pro-inflammatory factors such as IL-1β, IL-6, IL12 and TNF-α, which promote M1 macrophage polarization and bone resorption. MiR-23a targeted JAK1 and STAT6, and then inhibits the polarization of M2 macrophages.