Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression

Zhang, H.; Wang, L.; Cui, J.; Wang, S.; Han, Y.; Shao, H.; Wang, C.; Hu, Y.; Li, X.; Zhou, Q.; Guo, J.; Zhuang, X.; Sheng, S.; Zhang, T.; Zhou, D.; Chen, J.; Wang, F.; Gao, Q.; Jing, Y.; Chen, X.; Su, J.

doi:10.1101/2022.03.17.484053

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bioRxiv · 10.1101/2022.03.17.484053

Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression

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Abstract

Abnormal subchondral bone remodeling featured by over-activated osteoclastogenesis leads to articular cartilage degeneration and osteoarthritis (OA) progression, but the mechanism is still unclear. In this study, we used lymphocyte cytosolic protein 1 (Lcp1) knock-out mice to suppress subchondral osteoclast formation in mice OA model with anterior cruciate ligament transection (ACLT) and Lcp1-/- mice showed decreased bone remodeling and sensory innervation in subchondral bone accompanied by retarded cartilage degeneration. For mechanisms, in wildtype mice with ACLT the activated osteoclasts in subchondral bone induced type-H vessels and elevated oxygen concentration which ubiquitylated hypoxia-inducible factor 1 (HIF-1), vital for maintaining chondrocyte homeostasis in articular chondrocytes and led to cartilage degeneration. Deletion of Lcp1 impeded osteoclast-mediated angiogenesis, which maintained the low levels of oxygen partial pressure (pO2) in subchondral bone as well as the whole joint and delayed the OA progression. Stabilization of HIF-1 delayed cartilage degeneration and knockdown of Hif1a abolished the protective effects of Lcp1 knockout. Notably, we identified a novel subgroup of hypertrophic chondrocytes highly associated with OA by single cell sequencing analysis of human articular chondrocytes. Lastly, we showed that Oroxylin A, an Lcp1-encoded protein L-plastin (LPL) inhibitor, could alleviate OA progression. In conclusion, maintaining hypoxic environment in subchondral bone is an attractive strategy for OA treatment. TeaserInhibiting subchondral osteoclastogenesis alleviates OA progression via maintaining joint hypoxia environment.

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Zhang, H., Wang, L., Cui, J., Wang, S., Han, Y., Shao, H., Wang, C., Hu, Y., Li, X., Zhou, Q., Guo, J., Zhuang, X., Sheng, S., Zhang, T., Zhou, D., Chen, J., Wang, F., Gao, Q., Jing, Y., Chen, X., Su, J.. 2022-03-18. Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression. https://doi.org/10.1101/2022.03.17.484053

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