HDAC6 inhibition regulates substrate stiffness-mediated inflammation signaling in chondrocytes

Acta Biochim Biophys Sin (Shanghai). 2023 Dec 25;55(12):1987-1998. doi: 10.3724/abbs.2023144.

Abstract

Osteoarthritis (OA) is a chronic disease and is difficult to cure. Chondrocytes are highly mechanosensitive. Therefore, mechanical therapies have received attention as a therapeutic direction for OA. The stiffness, as a critical cue of the extracellular matrix (ECM), affects cell growth, development, and death. In this study, we use polydimethylsiloxane (PDMS) to create substrates with varying stiffness for chondrocyte growth, interleukin-1β (IL-1β) treatment to mimic the inflammatory environment, and Tubastatin A (Tub A) to inhibit histone deacetylase 6 (HDAC6). Our results show that stiff substrates can be anti-inflammatory and provide a better matrix environment than soft substrates. Inhibition of HDAC6 improves the inflammatory environment caused by IL-1β and coordinates with inflammation to spread the chondrocyte area and primary cilia elongation. Without IL-1β and Tub A treatments, the length of the primary cilia rather than frequency is stiffness-dependent, and their length on stiff substrates are greater than that on soft substrates. In conclusion, we demonstrate that stiff substrates, inflammation, and inhibition of HDAC6 enhance the mechanosensitivity of primary cilia and mediate substrate stiffness to suppress inflammation and protect the matrix.

Keywords: HDAC6; chondrocyte; inflammation; matrix metabolism; primary cilia; substrate stiffness.

MeSH terms

  • Chondrocytes* / metabolism
  • Histone Deacetylase 6 / metabolism
  • Histone Deacetylase 6 / therapeutic use
  • Humans
  • Inflammation / metabolism
  • Interleukin-1beta / metabolism
  • Osteoarthritis* / metabolism
  • Signal Transduction

Substances

  • Histone Deacetylase 6
  • Interleukin-1beta
  • HDAC6 protein, human

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 12272252 and 11872263) and the Fundamental Research Program of Shanxi Province (No. 202203021211124).