Summary: Osteoarthritis (OA) is a painful disease that is one of the most common causes of disability in the world. Despite the global burden of OA, disease-modifying osteoarthritis drugs (DMOADs) are still not available for clinical use. In recent years, there has been a large shift in the understanding of OA as a “wear and tear” disease to an inflammatory disease. The underlying pathomechanisms involving biochemical crosstalk among cartilage, synovium and bone have been demonstrated through various studies using imaging techniques and biomarkers. Avocado/soybean unsaponifiables (ASU; Piascledine) modulate OA pathogenesis and prevent cartilage degradation. Chondroprotective effects are mediated by inhibition of inflammatory cytokines similar to that observed in rheumatoid arthritis (RA), such as interleukins (IL-1, IL-6) and tumor necrosis factor (TNF-α). At the clinical level, ASU reduces pain and stiffness while improving joint function, resulting in decreased doses of analgesics.