accepted that defining OA subgroups based on risk factors is too simple, so it is of high clinical interest to identify specific OA phenotypes (subgroups of patients with similar clinically observable characteristics, i.e. genetic predispositions combined with environmental factors leading to tibiofemoral OA) and endotypes (disease subtypes defined functionally and pathologically by a molecular mechanism, i.e. different mechanisms leading to the same phenotype as tibiofemoral OA), which are the basis of accurate prognosis and development of personalized therapies 5. Several attempts have been made to group and identify OA phenotypes according to pathobiological mechanisms. Felson defines criteria for characterizing OA phenotypes via an epidemiological approach 4. He discriminates between generalized arthritis and joint-specific OA, secondary and primary OA, and incident and progressive OA. Another intriguing perspective is presented by Berenbaum et al., who provide a novel definition of OA as a “mismatch disease” commonly referred to by evolutionary biologists 6. This is defined as a condition that is more common today than in the past because the human body is not well adapted to certain features of modern environments. These features are high levels of physical inactivity, chronic low-grade inflammation, high body mass index, and obesogenic diets (processed foods which are high in sugar and saturated fat and low in fiber content). Other distinctions include the following phenotypes: chronic pain with central sensitization, inflammation, metabolic syndrome, bone and cartilage metabolism, and mechanical and minimal joint disease 7. Deveza et al. divide according to mechanistic subgroups including senescence, inflammation, pain, and metabolic endotypes 5. However, one thing has to be kept in mind when trying to define subgroups of OA. Although OA can be initiated by multiple factors at multiple sites, mechanical overloading is still the key feature of its pathogenesis. Joint tissues are sensitive to physical stimuli, and OA may result from excessively aberrant or physiologically normal mechanical stresses on initially healthy or pathologically impaired articular cartilage, bone, and ligaments, respectively 8. Brandt et al. pointed out in a commentary that they feel all OA is secondary due to the accumulation of intra-articular (i.a.) stress and all OA is primarily driven by mechanical stress on the joint 9. They postulate a basic mechanical etiopathogenesis for common OA and would rather categorize it on the basis of the underlying mechanical abnormality like post-traumatic, failure to absorb repetitive impulsive loading, and congenital or developmental anatomic incongruities. This review will select key OA pheno-endotypes according to relevant literature and current clinical trials/therapies that have been the most promising targets for recent clinical or pre-clinical studies. OA is characterized by the degradation of articular cartilage and bone matrix components. Among the earliest are type II collagen and the proteoglycan aggrecan, leading to the loss of cartilage structure and function 10, 11. Cartilage matrix degeneration products are well investigated for drug target discovery. Several key anabolic and catabolic pathway enzymes are dysregulated in OA cartilage, providing the opportunity to identify and validate new drug targets 12. To this end, novel combinations addressing existing known targets may be identified. This also includes combinations of therapeutics that are anti-catabolic and those that target anabolic signaling pathways. If investigated, this might lead to identifying novel efficacious add-ons from combining known drugs and targets. For better classification, there should be discrimination between disease-modifying OA drugs (DMOADs), which target pathways of cartilage catabolism and anabolism, and regenerative strategies based on stem cells and their components. Anabolic drug: sprifermin A promising anabolic DMOAD is sprifermin, which is a truncated