UBX0101, which selectively kills senescent cells, attenuated the development of post-traumatic OA, reduced pain and the production of SASP factors, and improved the development, phenotype, and function of human OA chondrocytes in 3D pellet culture. The half-life of UBX0101 was low, preventing systemic exposure, but was still effective in blocking cartilage degradation by eliminating senescent cells rather than blocking their SASP secretion. Targeting cell cycle inhibitors appears to be an intriguing new strategy to halt OA progression by addressing a risk factor, aging, that is closely associated to OA. Redox signal pathways and osteoarthritis An important therapeutic target might be redox-signaling pathways and associated mitochondrial dysfunction in OA. It is accepted that increasing levels of ROS contribute to age-related diseases by promoting cellular dysfunction and abolishing physiological cell signaling pathways 142. The prevention of mitochondrial peroxiredoxin (PRX) 3 hyperoxidation-induced expression of mitochondrial catalase abrogated p38-mediated cell death and restored homeostatic signaling to maintain the viability of aging chondrocytes 143. Another promising target could be superoxide dismutase 2 (Sod2), as deletion of Sod2 enhanced the severity of OA in mice 144. Another interesting target for counteracting oxidative stress-induced tissue damage might be nuclear receptor erythroid 2 related factor (Nrf2). Nrf2 is a key transcription factor that regulates the expression of phase II antioxidant enzymes. These enzymes protect against oxidative stress and tissue damage. Cai and colleagues explored the role of Nrf2 in OA pathogenesis and the effects of Nrf2 acetylation for histone deacetylase inhibitor (HDACi) protection. For this, they took advantage of two murine OA models: i.a. injection of MIA and destabilization of the medial meniscus (DMM) 145. In order to analyze the efficacy of HDACi on protection from cartilage damage, a pan-HDACi, trichostatin A (TSA), was applied. TSA promoted the induction of Nrf2 downstream proteins in mouse joint tissues and reduced the expression of OA-associated proteins like several MMPs and pro-inflammatory cytokines. TSA markedly ameliorated the cartilage damage in both OA models but offered no significant protection in Nrf2-knockout mice, suggesting that the protective effect of HDACi on OA progression was Nrf2 dependent. Addressing redox-signaling pathways and mitochondrial dysfunction will enable exciting novel strategies to combat cellular senescence in general and thereby eliminate a major risk factor for OA: age. Antioxidants may also have bone-protective effects in OA pathology. Using a spontaneous OA model, the STR/Ort mice, Javaheri et al. treated these mice for 3 months with SFX-01®, a synthetic stable variant of sulforaphane, a naturally occurring antioxidant 146. SFX-01® treatment both modifies bone architecture in the STR/Ort mice and likely reduces OA pain and improves gait without improving articular cartilage lesion severity and occurrence of osteophytes in the joints of these mice. These findings strengthen the possibility that bone-targeting therapies with antioxidants may have some merit and exert osteotrophic effects possibly not only in OA. For a few years, a novel concept considered OA as a multi-faceted disease involving the whole joint and not only cartilage or synovium. This offers new options to identify and develop novel therapeutics and to re-profile candidate drugs. Recent advances in OA pathology have enlightened key roles of several new pathways, which can be targeted. However, as OA is a highly heterogeneous disease, a single therapeutic targeting a single joint tissue may not be effective and no “one size fits all” drug/therapy will ever be developed. Improved patient stratification in combination with advanced DMOADs and cell-based therapies might lead to the development of personalized OA therapeutics. Attention to temporal changes in disease progression like the transition from high