Suppression of murine osteoarthritis by 4‐methylumbelliferone
Open Access
- 27 November 2019
- journal article
- research article
- Published by Wiley in Journal of Orthopaedic Research
- Vol. 38 (5), 1122-1131
- https://doi.org/10.1002/jor.24541
Abstract
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, 2020Keywords
Funding Information
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR072682)
This publication has 32 references indexed in Scilit:
- Hyaluronan synthase 2 (HAS2) overexpression diminishes the procatabolic activity of chondrocytes by a mechanism independent of extracellular hyaluronanJournal of Biological Chemistry, 2019
- The pericellular hyaluronan of articular chondrocytesMatrix Biology, 2018
- 4-Methylumbelliferone Diminishes Catabolically Activated Articular Chondrocytes and Cartilage Explants via a Mechanism Independent of Hyaluronan InhibitionPublished by Elsevier BV ,2016
- Gene expression changes in damaged osteoarthritic cartilage identify a signature of non-chondrogenic and mechanical responsesOsteoarthritis and Cartilage, 2016
- Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritisOsteoarthritis and Cartilage, 2015
- Emerging regulators of the inflammatory process in osteoarthritisNature Reviews Rheumatology, 2014
- Mouse Models of Osteoarthritis: Surgical Model of Posttraumatic Osteoarthritis Induced by Destabilization of the Medial MeniscusMethods in Molecular Biology, 2014
- The role of aggrecan in normal and osteoarthritic cartilageJournal of Experimental Orthopaedics, 2014
- The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouseOsteoarthritis and Cartilage, 2007
- The role of the chondrocyte in osteoarthritisArthritis & Rheumatism, 2000