Mechanical loading mitigates osteoarthritis symptoms by regulating endoplasmic reticulum stress and autophagy

Zheng, Weiwei; Li, Xinle; Liu, Daquan; Li, Jie; Yang, Shuang; Gao, Zhe; Wang, Zhaonan; Yokota, Hiroki; Zhang, Ping

doi:10.1096/fj.201801851r

Cited by 59 publications

(38 citation statements)

References 56 publications

(66 reference statements)

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“…The right hindlimb was shaved and sterilized with 70% of alcohol solution prior to generation of a 20 mm incision to expose the right knee joint. The medial collateral ligament was transected and the articular cavity was opened to allow for removal of the medial meniscus from its anterior attachment to the tibia . The surgery site was washed with sterile saline to remove tissue debris, and the incision was closed.…”

Section: Methodsmentioning

confidence: 99%

“…The medial collateral ligament was transected and the articular cavity was opened to allow for removal of the medial meniscus from its anterior attachment to the tibia. 24 The surgery site was washed with sterile saline to remove tissue debris, and the incision was closed. After finishing surgery on the right knee, the same procedure was conducted on the left knee.…”

Section: Oa Surgerymentioning

confidence: 99%

“…The moderately changing pressure may generate fluid flow in a lacuna canalicular network in bone cortex, and activate anabolic genes in bone . In our previous studies, we have shown that knee loading is effective in enhancing healing of bone wounds in a femur neck, promoting longitudinal bone growth, preventing bone loss in femoral head necrosis, reducing bone loss in an OP mouse model, and preventing tissue degeneration in OA . However, the role of knee loading on OPOA is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Knee loading repairs osteoporotic osteoarthritis by relieving abnormal remodeling of subchondral bone via Wnt/β‐catenin signaling

Zheng

Ding

et al. 2020

FASEB j.

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Oa Surgerymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Knee loading repairs osteoporotic osteoarthritis by relieving abnormal remodeling of subchondral bone via Wnt/β‐catenin signaling

Zheng

Ding

et al. 2020

FASEB j.

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“…Recently, autophagy has been found to be involved in many biological processes in a large number of organisms, and autophagy may be involved in the aging and degeneration of articular cartilage in OA [30,31]. To explore whether PAR2 was involved in autophagy of articular cartilage, immunohistochemistry were performed to assess the expressions of LC3-II and P62 related to autophagy.…”

Section: Down-regulation Of Par2 Promoted Autophagy In Cartilage Tissmentioning

confidence: 99%

Down-regulation of protease-activated receptor 2 ameliorated osteoarthritis in rats through regulation of MAPK/NF-κB signaling pathwayin vivoandin vitro

et al. 2020

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Recently, protease-activated receptor 2 (PAR2) has been proved to be involved in the inflammatory response including osteoarthritis (OA). In the present study, we found that PAR2 antagonist could remarkably improve the pathological condition of OA rats in vivo. In addition, we also found that PAR2 antagonist could suppress the production of inflammatory factors (TNF-α and Cox-2), decrease the levels of MMP-1 and MMP-13, and restrain the levels of P62 proteins and aggravate the expression of LC3-II both in vivo and in vitro. Besides, in vitro, PAR2 antagonist could increase the proliferation and colony formation of chondrocytes induced with IL-1β. Moreover, PAR2 antagonist could decrease the expression of expressions of p-p38, p-IκBα and p-NF-κB in vitro. However, PAR2 agonist exhibited the opposite effects. Furthermore, SB203580, a p38 MAPK inhibitor, could remarkably promote the proliferation of chondrocytes induced with IL-1β, could alleviate the production of TNF-α and Cox-2, could down-regulate the protein expressions of MMP-1 and MMP-13, and could decrease the expression of P62 and increase the expressions of LC3-II of chondrocytes induced with IL-1β. Importantly, SB203580 could reverse the effects of PAR2 agonist on the functions of chondrocytes induced with IL-1β. Taken together, the present data suggest that down-regulation of PAR2 can ameliorate OA through inducing autophagy via regulation of MAPK/NF-κB signaling pathway in vivo and in vitro, and PAR2 can be considered as a potential candidate to treat OA.

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“…After sacri ce, the femur and tibia were washed with MEM-α (Thermo Fisher Scienti c) for collecting BMSCs. The cells were isolated by centrifugation using a Ficoll low-density gradient and cultured in MEMα containing 10% FBS [33].…”

Section: Isolation Of Bone Marrow Mesenchymal Stem Cells and Their Cumentioning

confidence: 99%

Mechanical Loading Prevents Obesity-Associated Bone Loss by Maintaining the Balance between Adipocytes and Osteoblasts

Liu

et al. 2020

Preprint

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Background: Globally increasing obesity is closely linked to bone homeostasis. Maintaining the balance between differentiate of adipocytes and osteoblasts from bone marrow mesenchymal stem cells (BMSCs) is important for bone homeostasis. While mechanical loading has been shown to improve bone remodeling by promoting osteoblast differentiation, little is known about its effects on obesity-associated bone loss. Methods: Using obese mice induced by high-fat diet and ovariectomy (OVX), the effects of mechanical loading in a form of knee loading (1 N, 5 Hz, 6 min/day) was applied with for 4 weeks. The mice were sorted into five groups: standard diet control (SC), high-fat diet control (HF), HF and loading (HFL), HF and ovariectomy (HO), and HO and loading (HOL). Femurs were harvested for histomorphometry analysis. Bone marrow-derived cells were isolated to examine the banlance between differentiation of adipocytes and osteoblasts. Immunohistochemical analyses and Western blotting analyses were performed to evaluate markers for adipocytes, osteoblasts, and Wnt signaling.Results: High-fat diet presented higher body weight, body fat, and body mass index (BMI), as well as bone loss than standard diet, and the detrimental changes in OVX mice were even higher. The daily application of knee loading significantly decreased BMI, the numbers and perimeter of adipocytes, and the differentiation of adipocytes. The expression of C/EBPα and PPARγ were suppressed by knee loading. The loaded group also presented a significant increase in bone mineral density and contents, and the circumference of trabecular bone. Regarding osteoblasts, knee loading enhanced the number of osteoblasts on bone surface, differentiation of osteoblasts, and the level of Runx2 and ALP. Furthermore, Wnt signaling involved in the effect of knee loading on attenuating obesity-induced bone loss. Conclusions: This study supported evidence that knee loading offers a new therapeutic option to prevent obesity-related bone loss by altering the balance between adipocytes and osteoblasts in the bone marrow, and the effect is associated with Wnt signaling.

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Mechanical loading mitigates osteoarthritis symptoms by regulating endoplasmic reticulum stress and autophagy

Cited by 59 publications

References 56 publications

Knee loading repairs osteoporotic osteoarthritis by relieving abnormal remodeling of subchondral bone via Wnt/β‐catenin signaling

Knee loading repairs osteoporotic osteoarthritis by relieving abnormal remodeling of subchondral bone via Wnt/β‐catenin signaling

Down-regulation of protease-activated receptor 2 ameliorated osteoarthritis in rats through regulation of MAPK/NF-κB signaling pathwayin vivoandin vitro

Mechanical Loading Prevents Obesity-Associated Bone Loss by Maintaining the Balance between Adipocytes and Osteoblasts

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