ADAMTS5, short for A disintegrin and metalloproteinase with thrombospondin motifs 5, is a protease that cleaves chondroitin sulfate proteoglycans such as versican [1]. It is involved in multiple biological processes, and its dysregulation is associated with various diseases. Multiple molecular signaling pathways, including Runx2, Fgf2, Notch, Wnt, NF-κB, YAP/TAZ, and other inflammatory signaling pathways, modulate ADAMTS5 expression [2].

In heart failure, ADAMTS proteases are critical for versican degradation in the heart, and versican accumulation is associated with impaired cardiac function. 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 [1]. In osteoarthritis, ADAMTS5 is the major aggrecanase-degrading articular cartilage matrix, and its over-activation, due to senescence, inheritance, inflammation, and mechanical stress, contributes to the pathogenesis of OA [2]. In the mandibular condyle, Adamts5-deficient mice show an increase in trabecular separation and reduction of trabecular thickness and bone volume fraction, indicating its requirement for normal trabeculated bone development [3].

In conclusion, ADAMTS5 plays essential roles in proteoglycan remodeling in the heart, cartilage degradation in osteoarthritis, and trabeculated bone development in the mandibular condyle. Gene-knockout mouse models, such as Adamts5ΔCat and Adamts5-deficient mice, have been crucial in revealing these functions, providing insights into the pathogenesis of related diseases and potential therapeutic targets.

References:

1. Barallobre-Barreiro, Javier, Radovits, Tamás, Fava, Marika, Merkely, Béla, Mayr, Manuel. 2021. Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling. In Circulation, 144, 2021-2034. doi:10.1161/CIRCULATIONAHA.121.055732. https://pubmed.ncbi.nlm.nih.gov/34806902/

2. Jiang, Lejian, Lin, Jiachen, Zhao, Sen, Wang, Yue, Lin, Mao. 2021. ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies. In Frontiers in molecular biosciences, 8, 703110. doi:10.3389/fmolb.2021.703110. https://pubmed.ncbi.nlm.nih.gov/34434966/

3. Rogers-DeCotes, A W, Porto, S C, Dupuis, L E, Kern, C B. 2021. ADAMTS5 is required for normal trabeculated bone development in the mandibular condyle. In Osteoarthritis and cartilage, 29, 547-557. doi:10.1016/j.joca.2021.01.005. https://pubmed.ncbi.nlm.nih.gov/33561540/