Dysregulated lysosomal exocytosis drives protease-mediated cartilage pathogenesis in multiple lysosomal disorders

The classic view of the lysosome as a static recycling center has been replaced with one of a dynamic and mobile hub of metabolic regulation. This revised view raises new questions about how dysfunction of this organelle causes pathology in inherited lysosomal disorders. Here we provide evidence for increased lysosomal exocytosis in the developing cartilage of three lysosomal disease zebrafish models with distinct etiologies. Dysregulated exocytosis was linked to altered cartilage development, increased activity of multiple cathepsin proteases, and cathepsin- and TGFβ-mediated pathogenesis in these models. Moreover, inhibition of cathepsin activity or direct blockade of exocytosis with small molecule modulators improved the cartilage phenotypes, reinforcing a connection between excessive extracellular protease activity and cartilage pathogenesis. This study highlights the pathogenic consequences in early cartilage development arising from uncontrolled release of lysosomal enzymes via exocytosis, and suggests that pharmacological enhancement of this process could be detrimental during tissue development.