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FASEB J. 2019 Mar;33(3):4077-4088. doi: 10.1096/fj.201801851R. Epub 2018 Nov 28.

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

Zheng W1, Li X1,2,3, Liu D1,2,3, Li J1,2, Yang S1,2, Gao Z1, Wang Z1, Yokota H4, Zhang P1,2,3,4.

Author information

1
Department of Anatomy and Histology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
2
Tianjin Economic-Technological Development Area, International Cardiovascular Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
3
Key Laboratory of Hormones and Development, Ministry of Health, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, China.
4
Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indiana, USA.

Abstract

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.

KEYWORDS:

OA; P62; eIF2alpha; knee load; non-invasive physical therapy

PMID:
30485126
PMCID:
PMC6404578
[Available on 2020-03-01]
DOI:
10.1096/fj.201801851R

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