ADAMTS5, also known as A disintegrin and metalloproteinase with thrombospondin motifs 5, is a protease that cleaves chondroitin sulfate proteoglycans like versican. It is involved in extracellular matrix (ECM) remodeling pathways and is of great biological importance in various physiological and pathological processes [1,2,3,6]. Genetic models, such as knockout mouse models, have been valuable in studying its functions.

In heart failure, in Adamts5ΔCat mice (lacking the catalytic domain of ADAMTS5), angiotensin II infusion led to aggravated versican build-up, hyaluronic acid disarrangement, and reduced levels of integrin β1, filamin A, and connexin 43, along with reduced ejection fraction and impaired global longitudinal strain, suggesting ADAMTS5 is critical for versican degradation in the heart [1].

In osteoarthritis, ADAMTS5 is the major aggrecanase-degrading articular cartilage matrix, and its overactivation due to factors like senescence, inheritance, inflammation, and mechanical stress contributes to the pathogenesis. Monoclonal antibodies and small-molecule inhibitors against ADAMTS5 have shown pre-clinical benefits [2].

In proliferative diabetic retinopathy, ADAMTS5 promotes neovascularization via autophagic degradation of PEDF, as inhibiting ADAMTS5 alleviated pathological angiogenesis in oxygen-induced retinopathy mice [4].

In the context of Treponema pallidum subspecies pallidum invading the central nervous system, Tp increased ADAMTS5 expression in human cortical microvascular endothelial cells, and inhibiting ADAMTS5 mitigated barrier permeability changes [5].

In mandibular condyle development, Adamts5-deficient mice had altered trabecular bone parameters, indicating ADAMTS5 is required for normal trabeculated bone development [6].

In conclusion, ADAMTS5 plays essential roles in ECM remodeling, affecting processes like cardiac function, cartilage integrity, neovascularization, blood-brain barrier permeability, and bone development. The use of ADAMTS5 KO/CKO mouse models has significantly contributed to understanding its functions in heart failure, osteoarthritis, proliferative diabetic retinopathy, neurosyphilis, and mandibular condyle development, providing insights into disease mechanisms and potential therapeutic targets.