Wheel-Running Exercise Protects Ovariectomized Mice from Bone Loss via IFN-γ-Mediated Suppression of the NF-κB and MAPK Pathways

Abstract

Physical exercise is recommended as a preventative approach for osteoporosis; however, the effect of physical exercise on bone mass remains controversial. Additionally, the immune regulation of physical exercise on bone mass remains unclear. To determine whether wheel-running (WR) exercise contributes to improving bone mineral density (BMD) and investigate the involved immune mechanism, ovariectomized (OVX) and sham-operated mice were treated with 8 weeks of WR exercise. The distal femurs of the mice were sequentially scanned, reconstructed, and analyzed using microcomputed tomography and related software to assess BMD and bone microarchitecture. Flow cytometry assays were applied to investigate alterations in immune cells and inflammatory cytokines. In vitro, osteoclast differentiation was conducted to determine the effect of IFN-γ on osteoclastogenesis and the underlying mechanism. As a result, trabecular parameters were decreased in the OVX mice compared with the sham group. However, WR exercise significantly improved the deterioration in the bone microarchitecture of the OVX mice with an increase of 60.00% in BMD, 55.18% in bone volume, 66.67% in trabecular number, 32.52% in trabecular thickness, and a decrease of 19.44% in trabecular separation. Similarly, WR exercise increased the proportion of CD8+ T cells from 7.26 ± 1.71 % to 10.23 ± 1.35 % in the spleen and from 1.62 ± 0.54 % to 2.38 ± 0.43 % in the bone marrow of the OVX mice ( P < 0.05 ). The expression of IFN-γ was also increased in the OVX + WR mice compared with the OVX mice ( 1.65 ± 0.45 % vs. 2.26 ± 0.34 % , P < 0.05 ). In vitro studies demonstrated an inhibitory effect of IFN-γ on osteoclastogenesis in a dose- and time-dependent manner. Meanwhile, the classical NF-κB and MAPK pathways were found to be critical in IFN-γ-mediated inhibition of osteoclast differentiation. In conclusion, our study discovered that WR exercise rescued bone loss in the OVX mice in an IFN-γ-mediated immunomodulatory manner. After WR exercise, IFN-γ expression was restored by activated CD8+ T cells, consequently leading to the inhibition of osteoclastogenesis and the recovery from bone loss through the NF-κB and MAPK pathways.

Osteoporosis: interferon-gamma-mediated bone remodeling in osteoimmunology

“…In an IFN-γ-mediated immunomodulatory approach, Hao Shen et al. demonstrated that WR exercise prevented bone loss in OVX mice ( 209 ). Activated CD8 T lymphocytes restored IFN-γ expression after WR exercise, which prevented OC formation and restored bone loss via NF-κB and MAPK pathways.…”

The role and regulation mechanism of Chinese traditional fitness exercises on the bone and cartilage tissue in patients with osteoporosis: A narrative review

“…In addition, the LRP family proteins and Wnt/β-catenin pathway are regulated by exercise, which improves bone remodeling, bone mass recovery, and bone stiffness in rats with disuse osteoporosis (Chen et al, 2016;Jia et al, 2019). Roller exercises prevent osteoporosis by activating CD8 T cells to release IFN-γ, which exhibits the effects of inhibiting osteoclast formation and recovering bone loss through NF-κB and MAPK pathways (Shen et al, 2022) (Figure 1).…”

Regulation of bone health through physical exercise: Mechanisms and types

“…By measuring and comparing the BMD of postmenopausal athletes with different levels of physical activity, Yang et al concluded that long-term exercise effectively prevented bone loss in female athletes and improved their musculoskeletal fitness (87). In addition, wheelrunning exercise prevented bone loss in OVX mice (56). RNAsequencing technology in the peripheral blood mononuclear cells (PBMCs) of OVX rats was also used to investigate the effect of moderate-intensity treadmill exercise on the sensitive genes related to bone mass (88).…”

“…The majority of proinflammatory cytokines such as IL-6, TNF-α, IL-1, and IFN-γ play a pivotal role in the treatment of osteoporosis through exercise ( 54 – 56 ). Exercise may improve inflammation by upregulating anti-inflammatory factors, which may have an effect on bone metabolism ( 57 ).…”

“…Inflammatory bone loss in the OVX mice associated with IFN-γ was rescued by wheel-running exercise. After that, CD8 T cells were activated and then secreted IFN-γ, which induced the NF-κB/MAPK pathway activation and inhibited osteoclastogenesis ( 56 ). After HA/β-TCP biomaterials were implanted into the mice, IFN-γ levels increased, which helped to treat osteoporotic fractures ( 59 ).…”