The extracellular matrix (ECM) is a dynamic and organised extracellular network assembled from proteins and carbohydrates exported from the cell. The ECM is critical for multicellular life, providing spatial and temporal cellular cues to maintain tissue homeostasis. Consequently, ECM production must be carefully balanced with turnover to ensure homeostasis; ECM dysfunction culminates in disease. Hsp90 is a molecular chaperone central to protein homeostasis, including in the ECM. Intracellular and extracellular Hsp90 isoforms collaborate to regulate the levels and status of proteins in the ECM via multiple mechanisms. In so doing, Hsp90 regulates ECM dynamics, and changes in Hsp90 levels or activity support the development of ECM-related diseases, like cancer and fibrosis. Consequently, Hsp90 levels may have prognostic value, while inhibition of Hsp90 may have therapeutic potential in conditions characterised by ECM dysfunction.

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