Suppression of murine osteoarthritis by 4‐methylumbelliferone

Using in vitro models, we previously reported that 4‐methylumbelliferone (4‐MU) blocked many of the pro‐catabolic features of activated chondrocytes. 4‐MU also blocked safranin O loss from human cartilage explants exposed to interleukin 1β (IL1β) in vitro. However, the mechanism for this chondroprotective effect was independent of the action of 4‐MU as a hyaluronan (HA) inhibitor. Interestingly, overexpression of HA synthase 2 (HAS2) also blocked the same pro‐catabolic features of activated chondrocytes as 4‐MU via a mechanism independent of extracellular HA accumulation. Data suggest that altering UDP‐sugars may be behind these changes in chondrocyte metabolism. However, all of our previous experiments with 4‐MU or HAS2 overexpression were performed in vitro. The purpose of this study was to confirm whether 4‐MU was effective at limiting the effects of osteoarthritis (OA) on articular cartilage in vivo. The progression of OA was evaluated after destabilization of the medial meniscus (DMM) surgery on C57BL/6 mice in the presence or absence of 4‐MU‐containing chow. Mice fed 4‐MU after DMM surgery exhibited significant suppression of OA starting from an early stage in vivo. Mice fed 4‐MU exhibited lower OARSI scores after DMM; reduced osteophyte formation and reduced MMP3 and MMP13 immunostaining. 4‐MU also exerted pronounced chondroprotective effects on murine joint cartilage exposed to IL1β in vitro and, blocked IL1β‐enhanced lactate production in cartilage explants. Therefore, 4‐MU is effective at significantly reducing the loss of proteoglycan and reducing MMP production both in vitro and in vivo as well as cartilage damage and osteophyte formation in vivo after DMM. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. 38:1122‐1131, 2020