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Osteoarthritis (OA) is a major health problem, characterized by progressive cartilage degeneration. Previous works have shown that mechanical loading can alleviate OA symptoms by suppressing catabolic activities. This study evaluated whether mechanical loading can enhance anabolic activities by facilitating the recruitment of stem cells for chondrogenesis. We evaluated cartilage degradation in a mouse model of OA through histology with H&E and safranin O staining. We also evaluated the migration and chondrogenic ability of stem cells using in vitro assays, including immunohistochemistry, immunofluorescence, and Western blot analysis. The result showed that the OA mice that received mechanical loading exhibited resilience to cartilage damage. Compared to the OA group, mechanical loading promoted the expression of Piezo1 and the migration of stem cells was promoted via the SDF-1/CXCR4 axis. Also, the chondrogenic differentiation was enhanced by the upregulation of SOX9, a transcription factor important for chondrogenesis. Collectively, the results revealed that mechanical loading facilitated cartilage repair by promoting the migration and chondrogenic differentiation of endogenous stem cells. This study provided new insights into the loading-driven engagement of endogenous stem cells and the enhancement of anabolic responses for the treatment of OA., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Osteoarthritis (OA) is a whole joint disorder that is characterized by cartilage damage and abnormal remodeling of subchondral bone. Injecting adipose-derived stem cells (ASCs) into the knee joint cavity can assist in repairing osteoarthritic joints, but their ability to migrate to the damaged site is limited. Our previous studies have shown that knee loading can improve the symptoms of OA, but the effect and mechanism of knee loading on the migration of ASCs in OA remain unclear. We employed a mouse model of OA in the knee and applied knee loading (1 N at 5 Hz for 6 min/day for 2 weeks) after the intra-articular injection of ASCs. The cartilage and subchondral bone repair were assessed by histopathological analysis. Immunofluorescence assays were also used to analyze the migration of ASCs. Using cell cultures, we evaluated the migration of ASCs using the transwell migration and wound healing assays. In vivo experiments showed that knee loading promoted the migration of ASCs, increased the local SDF-1 level, and accelerated the repair of the OA-damaged sites. Mechanistically, the observed effects were blocked by the SDF-1/CXCR4 inhibitor. The in vitro results further revealed that knee loading promoted the migration of ASCs and the inhibition of SDF-1/CXCR4 significantly suppressed the beneficial loading effect. The results herein suggested that the migration of ASCs was enhanced by knee loading through the SDF-1/CXCR4 regulatory axis, and mechanical loading promoted the joint-protective effect of ASCs., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Osteoarthritis (OA) is one of the most common chronic diseases, in which inflammatory responses in the articular cavity induce chondrocyte apoptosis and cartilage degeneration. While mechanical loading is reported to mitigate synovial inflammation, the mechanism and pathways for the loading-driven improvement of OA symptoms remain unclear. In this study, we evaluated the loading effects on M1/M2 polarization of synovial macrophages via performing histology, cytology, and molecular analyses. In the OA group, the cell layer of the synovial lining was enlarged with an increase in cell density. Also, M1 macrophages were polarized and proinflammatory cytokines were increased. In contrast, in the OA group with mechanical loading, cartilage degradation was reduced and synovial inflammation was alleviated. Notably, the M1 macrophages were diminished by mechanical loading, while M2 macrophages were increased. Furthermore, mechanical loading decreased the levels of proinflammatory cytokines, such as interleukin-1 beta and tumor necrosis factor-α, and suppressed PI3K/AKT/NF-κB signaling. Taken together, this study demonstrates that mechanical loading changes the ratio of M1 and M2 macrophages via regulation of PI3K/AKT/NF-κB signaling and provides cartilage protection in the mouse OA model., (© 2022 New York Academy of Sciences.)

Osteoporotic osteoarthritis (OPOA) is a common bone disease mostly in the elderly, but the relationship between Osteoporotic (OP) and osteoarthritis (OA) is complex. It has been shown that knee loading can mitigate OA symptoms. However, its effects on OPOA remain unclear. In this study, we characterized pathological linkage of OP to OA, and evaluated the effect of knee loading on OPOA. We employed two mouse models (OA and OPOA), and conducted histology, cytology, and molecular analyses. In the OA and OPOA groups, articular cartilage was degenerated and Osteoarthritis Research Society International score was increased. Subchondral bone underwent abnormal remodeling, the differentiation of bone marrow mesenchymal stem cells (BMSCs) to osteoblasts and chondrocytes was reduced, and migration and adhesion of pre-osteoclasts were enhanced. Compared to the OA group, the pathological changes of OA in the OPOA group were considerably aggravated. After knee loading, however, cartilage degradation was effectively prevented, and the abnormal remodeling of subchondral bone was significantly inhibited. The differentiation of BMSCs was also improved, and the expression of Wnt/β-catenin was elevated. Collectively, this study demonstrates that osteoporosis aggravates OA symptoms. Knee loading restores OPOA by regulating subchondral bone remodeling, and may provide an effective method for repairing OPOA., (© 2020 Federation of American Societies for Experimental Biology.)

Osteoarthritis (OA) is a disease characterized by cartilage damage and abnormal remodeling of subchondral bone. Our previous study showed that in the early stage of OA, knee loading exerts protective effects by suppressing osteoclastogenesis through Wnt signaling, but little is known about loading effects at the late OA stage. Endoplasmic reticulum (ER) stress and autophagy are known to be involved in the late OA stage. We determined the effects of mechanical loading on ER stress and autophagy in OA mice. One hundred seventy-four mice were used for a surgery-induced OA model. In the first set of experiments, 60 mice were devoted to evaluation of the role of ER stress and autophagy in the development of OA. In the second set, 114 mice were used to assess the effect of knee loading on OA. Histologic, cellular, microcomputed tomography, and electron microscopic analyses were performed to evaluate morphologic changes, ER stress, and autophagy. Mechanical loading increased phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and regulated expressions of autophagy markers LC3II/I and p62. Osteoarthritic mice also exhibited an elevated ratio of calcified cartilage to total articular cartilage (CC/TAC), and synovial hyperplasia with increased lining cells was found. At the early disease stage, subchondral bone plate thinning and reduced subchondral bone volume fraction (B.Ar/T.Ar) were observed. At the late disease stages, subchondral bone plate thickened concomitant with increased B.Ar/T.Ar. Mice subjected to mechanical loading exhibited resilience to cartilage destruction and a correspondingly reduced Osteoarthritis Research Society International score at 4 and 8 wk, as well as a decrease in synovitis and CC/TAC. While chondrocyte numbers in the OA group was notably decreased, mechanical loading restored chondrogenic differentiation. These results demonstrate that mechanical loading can retard the pathologic progression of OA at its early and late stages. The observed effects of loading are associated with the regulations of ER stress and autophagy.-Zheng, W., Li, X., Liu, D., Li, J., Yang, S., Gao, Z., Wang, Z., Yokota, H., Zhang, P. Mechanical loading mitigates osteoarthritis symptoms by regulating endoplasmic reticulum stress and autophagy.