JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA
Tong Wang
JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA
Kali Wiggins
JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA
Po Nien Lu
JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA
Christina Underwood
Biochemical Genetics Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA
Katarzyna Ochenkowska
Research Center, Centre hospitalier de l’Université de Montréal (CHUM), Montreal, Canada; Department of Neuroscience, Université de Montréal, Montréal, Canada
Eric Samarut
Research Center, Centre hospitalier de l’Université de Montréal (CHUM), Montreal, Canada; Department of Neuroscience, Université de Montréal, Montréal, Canada
Laura M. Pollard
Biochemical Genetics Laboratory, Greenwood Genetic Center, Greenwood, SC 29646, USA
Heather Flanagan-Steet
JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA; Corresponding author
Richard Steet
JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA; Corresponding author
Summary: 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.
