In December 2022, Gerwin et al published in Nature Medicine that the C-terminal portion of angiopoietin-like 3, called LNA043, has chondroprotective and cartilage-regenerative properties. Molecular data from an experimental medicine phase I study suggested potential efficacy in humans. Here, we respond to and complement a commentary from Vincent and Conaghan and discuss unresolved issues and the potential of this molecule as a disease-modifying osteoarthritis drug.