version of human FGF18 that induces chondrocyte proliferation and cartilage matrix production. The results of a phase Ib study of i.a. injected sprifermin in patients with symptomatic knee OA found a statistically significant dose-dependent reduction in loss of total femorotibial cartilage thickness compared to placebo after 12 months of follow up 13. Sprifermin is currently being studied in a phase II multicenter randomized dose-finding clinical study (clinicaltrials.gov: NCT01919164). The i.a. administration of 100 μg of sprifermin to participants with symptomatic radiographic knee OA every 6 or 12 months vs. placebo resulted in an improvement in total femorotibial joint cartilage thickness after a follow up period of 2 years. This improvement was statistically significant, but clinical importance was not clear. Application of a lower dose, 30 μg of sprifermin, every 6 or 12 months vs. placebo did not result in a significant difference and it was uncertain whether the response was long lasting Anabolic drug: BMP-7 Another approach was the application of BMP-7, where studies have shown a pro-anabolic effect, making BMP-7 a potential candidate to promote articular cartilage repair. Three clinical trials (two phase I and one phase II) investigated the administration of BMP-7 in patients with knee OA. Two trials were completed without results being posted (NCT01133613 and NCT01111045), and one was completed with results published (NCT00456157) 15. There was no dose-limiting toxicity identified in the latter study. Most adverse events were mild or moderate and were similar in placebo and BMP-7 groups. Notably, overall, the outcome of the BMP-7 group was similar to the placebo group, as both groups experienced a 20% improvement in pain Anti-catabolic drugs: MMP inhibitors Inhibition of MMPs, i.e. MMP-13 and aggrecanases such as ADAMTS-4 and -5, which are key proteases responsible for cartilage matrix degradation in OA 45, 46, might be another way to delay cartilage destruction. A human clinical trial (NCT00041756) involving knee OA patients receiving the MMP inhibitor PG-116800 (PG-530742), which has low affinity for both MMP-1 and MMP-7, was unfortunately terminated because of musculoskeletal toxicity 12 . The most frequent adverse effect was arthralgia (35% of patients), and 13% of patients reported hand adverse events (edema, palmar fibrosis, Dupuytren’s contracture, or persistent tendon thickness or nodules). As a result, MMP inhibitor PG-116800 has not been developed further as a treatment for knee OA 47. Other more MMP-13 selective compounds, such as CP-544439, AZD-8955, and WAY-170523, are under investigation, but clinical data have not been released yet 13. MMPs and aggrecanases are involved in cartilage matrix degradation, and a balanced activity of these proteases is critical for matrix homeostasis. An unbalanced protease activity favoring rapid cartilage matrix degradation in early OA pathogenesis might classify as an additional OA endotype, which then would qualify as a specific target for drug intervention. These data demonstrate that compounds such as sprifermin (FGF18) and BMP-7 have promising pro-anabolic effects on cartilage tissue, whereas the inhibition of catabolic factors such as proteases has not shown beneficial effects in cartilage so far owing to adverse effects . Regenerative therapies with stem cell A total of 144 clinical trials investigating the therapeutic impact of stem cells on OA and on cartilage trauma have been reported to date at www.clinicaltrials.gov, suggesting regenerative medicine may be a promising therapy for future OA management. At first, case reports described the transplantation of mesenchymal stem cells (MSCs) through an invasive approach (surgery). Later, the introduction of autologous MSCs within the joint by i.a. injection, which represents a less-invasive strategy, was reported to be feasible and safe. Indeed, after i.a. injection into SCID mice, MSCs engrafted directly in the injured site, which has