Changes to the extracellular ionic composition and osmolarity have profound effects on ECM metabolism by connective tissue cells. This has been demonstrated in articular cartilage and intervertebral disc explants, isolated chondrocytes,and chondrocytes cultured in alginate [45,67–69], as well asisolated intervertebral disc cells [70]. In articular cartilage,variations in medium osmolarity above or below that in nativenon-degenerate cartilage, inhibit optimal matrix GAG andprotein synthesis [45]. Alterations to osmolarity also closelyregulate the expression of genes encoding hyaline cartilageECM proteins, including collagen type II (COL2A1)andaggrecan (ACAN)[41] through the cartilage master regulatorSOX9 [71,72]. Raised osmolarity increases SOX9 mRNAstability and SOX9 protein production [41] and SOX9 also suppresses ADAMTS (A Disintegrin And Metalloproteinasewith Thrombospondin Motifs) activity [73]. Thischondrogenic transcription factor is therefore crucial for themaintenance of normal cartilage viability.