Mechanosensory and mechanotransductive processes mediated by ion channels in articular chondrocytes: Potential therapeutic targets for osteoarthritis

ABSTRACT

Articular cartilage consists of an extracellular matrix including many proteins as well as embedded chondrocytes. Articular cartilage formation and function are influenced by mechanical forces. Hind limb unloading or simulated microgravity causes articular cartilage loss, suggesting the importance of the healthy mechanical environment in articular cartilage homeostasis and implying a significant role of appropriate mechanical stimulation in articular cartilage degeneration. Mechanosensitive ion channels participate in regulating the metabolism of articular chondrocytes, including matrix protein production and extracellular matrix synthesis. Mechanical stimuli, including fluid shear stress, stretch, compression and cell swelling and decreased mechanical conditions (such as simulated microgravity) can alter the membrane potential and regulate the metabolism of articular chondrocytes via transmembrane ion channel-induced ionic fluxes. This process includes Ca²⁺ influx and the resulting mobilization of Ca²⁺ that is due to massive released Ca²⁺ from stores, intracellular cation efflux and extracellular cation influx. This review brings together published information on mechanosensitive ion channels, such as stretch-activated channels (SACs), voltage-gated Ca²⁺ channels (VGCCs), large conductance Ca²⁺-activated K⁺ channels (BK_Ca channels), Ca²⁺-activated K⁺ channels (SK_Ca channels), voltage-activated H⁺ channels (VAHCs), acid sensing ion channels (ASICs), transient receptor potential (TRP) family channels, and piezo1/2 channels. Data based on epithelial sodium channels (ENaCs), purinergic receptors and N-methyl-d-aspartate (NMDA) receptors are also included. These channels mediate mechanoelectrical physiological processes essential for converting physical force signals into biological signals. The primary channel-mediated effects and signaling pathways regulated by these mechanosensitive ion channels can influence the progression of osteoarthritis during the mechanosensory and mechanoadaptive process of articular chondrocytes.

KEYWORDS:

• Ion channel
• mechanical force
• articular chondrocyte
• membrane potential
• osteoarthritis

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81874017 and 81960403 and 82060405 and 82060413); National Science Foundation of Gansu Province of China (20JR5RA320); Lanzhou Science and Technology Plan Program (2018-3-52); Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital (CY2017-QN12, CY2017-ZD02); The Fundamental Research Funds for the Central Universities (lzujbky-2020-kb17).

Authors’s contributions

Kun Zhang, Yayi Xia and Lifu Wang conceived and designed the idea to this paper; Yuanjun Teng, Xuening Liu, Qiong Yi and Zhongcheng Liu participated in its design and coordination and supervised the paper. Yuanjun Teng, Dacheng Zhao, Dechen Yu and Xiangyi Chen collected and analyzed the references and drafted the paper. Bin Geng supervised the framework of the article. All authors read and approved the final version of the manuscript. Kun Zhang was the first author of this article. Kun Zhang and Lifu Wang contributed equally to this work.

Disclosure statement

There are no relevant financial or non-financial competing interests

Additional information

Funding

This work was supported by the The National Natural Science Foundation of China [81874017]; The National Natural Science Foundation of China [81960403]; The National Natural Science Foundation of China [82060405]; National Science Foundation of Gansu Province of China [20JR5RA320]; The National Natural Science Foundation of China [82060413]; Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital [CY2017-QN12]; Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital [CY2017-ZD02]; The Fundamental Research Funds for the Central Universities [lzujbky-2020-kb17]; Lanzhou Science and Technology Plan Program [2018-3-52].