Journal of orthopaedic translation · 2026
Hydrogen sulfide generated by cystathionine gamma lyase inhibits lysyl oxidase and protects against calcific tendinopathy.
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Faure Elodie, Bernabei Ilaria, Ehirchiou Driss, Michel Philipp, Kronenberg Daniel, Pap Thomas, Cirino Giuseppe, Stange Richard, Busso Nathalie, Nasi Sonia
Аннотация
BACKGROUND/OBJECTIVE: Increased lysyl oxidase (LOX) activity favors pathologic cartilage and vessel calcification. LOX promotes disease through enhanced collagen cross-linking, inflammation, reactive oxygen species (ROS) production, cell trans-differentiation, and fibrosis. This study investigates the therapeutic potential of cystathionine gamma lyase (CSE)-generated hydrogen sulfide (H2S) to inhibit tendon calcification by targeting LOX in human samples and murine models of calcific tendinopathy (CT).
METHODS: Human shoulder supraspinatus tendons with varying degrees of CT were analyzed using Alizarin Red staining and LOX and CSE immunohistochemistry to evaluate the correlation between CSE and LOX/calcification. Mechanistic studies were performed using wild-type (WT) and CSE knockout murine tenocytes cultured in calcification-inducing medium with or without H2S donors or the LOX inhibitor β-aminopropionitrile (BAPN). Achilles tendon CT was induced in WT and CSE knockout mice via surgical intervention or aging. Tendon calcification, LOX expression, biomechanical integrity, and transcriptomic changes were assessed. Persulfidation of total proteins and recombinant human LOX (rhLOX) was measured using the dimedone-switch method.
RESULTS: An inverse correlation between CSE levels and LOX/calcification was observed in human tendons and in the surgery-induced CT murine model. In murine tenocytes and in the aging murine model, CSE deficiency led to increased LOX expression, enhanced calcification, and reduced tendon biomechanical integrity.Transcriptomic analysis confirmed the negative association between CSE and LOX in murine CT. Mechanistically, H2S increased total cellular protein persulfidation, including rhLOX, resulting in inhibition of its enzymatic activity.
CONCLUSION: Dysregulated LOX activity is a key driver of calcific tendinopathy. CSE-generated H2S effectively suppresses LOX activity, highlighting its potential as a therapeutic strategy for CT and other calcification-related disorders.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study identifies LOX as a therapeutic target in CT and supports H2S as a promising treatment strategy for this condition.
METHODS: Human shoulder supraspinatus tendons with varying degrees of CT were analyzed using Alizarin Red staining and LOX and CSE immunohistochemistry to evaluate the correlation between CSE and LOX/calcification. Mechanistic studies were performed using wild-type (WT) and CSE knockout murine tenocytes cultured in calcification-inducing medium with or without H2S donors or the LOX inhibitor β-aminopropionitrile (BAPN). Achilles tendon CT was induced in WT and CSE knockout mice via surgical intervention or aging. Tendon calcification, LOX expression, biomechanical integrity, and transcriptomic changes were assessed. Persulfidation of total proteins and recombinant human LOX (rhLOX) was measured using the dimedone-switch method.
RESULTS: An inverse correlation between CSE levels and LOX/calcification was observed in human tendons and in the surgery-induced CT murine model. In murine tenocytes and in the aging murine model, CSE deficiency led to increased LOX expression, enhanced calcification, and reduced tendon biomechanical integrity.Transcriptomic analysis confirmed the negative association between CSE and LOX in murine CT. Mechanistically, H2S increased total cellular protein persulfidation, including rhLOX, resulting in inhibition of its enzymatic activity.
CONCLUSION: Dysregulated LOX activity is a key driver of calcific tendinopathy. CSE-generated H2S effectively suppresses LOX activity, highlighting its potential as a therapeutic strategy for CT and other calcification-related disorders.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study identifies LOX as a therapeutic target in CT and supports H2S as a promising treatment strategy for this condition.