Inhibition of cyclin-dependent kinase 8 modulates chondrocyte transition to hypertrophy and provides in vivo protection against spontaneous osteoarthritis

Abstract

Chondrocyte hypertrophy is a key hallmark of osteoarthritis (OA) that drives a multitude of whole-joint disease processes. There are no approved disease-modifying pharmaceuticals in clinical use, emphasising the urgent need for innovative therapeutics. Screening of a focussed chemical library using a novel in vitro platform discovered that inhibition of CDK8/19 mediator kinases modulated chondrocyte behaviours with potential to limit OA hallmarks. Transcriptomic analysis of various chondrogenic cell populations revealed that CDK8/19-inhibitor treatment upregulated pro-anabolic/anti-catabolic markers, downregulated markers of hypertrophy and protected from IL1β-induced extracellular matrix degradation. CDK8 was also found to be upregulated in chondrocytes in vitro following IL1β stimulation. This translated to human OA cartilage, where CDK8, MED12 and pSTAT1 were found to co-localise to cartilage lesions. Exposure to CDK8/19-inhibitor modified cell metabolism in hypertrophic chondrocytes and reduced inflammatory processes in THP-1-derived macrophages. CDK8/19-inhibitor treatment of the STR/Ort mouse corrected gait asymmetry and improved treadmill completion rates, whilst suppressing weight gain and serum OA biomarkers. Histological analyses of STR/Ort mouse knee joints revealed that in vivo CDK8/19-inhibitor treatment upregulated chondromodulin-1, matrillin-3 and enhanced proteoglycan deposition in the pericellular matrix of growth plate/articular cartilage. Micro computed tomography (µCT) showed that CDK8/19-inhibitor treatment modified chondrocyte endochondral behaviours to limit the number and density of mineralised growth plate bridges, which otherwise accumulate with age in STR/Ort mice. Collectively, these data highlight CDK8/19 inhibition as a promising disease-modifying strategy for targeting whole-joint disease in OA and, for the first time, show that CDK8/19 inhibition exerts pivotal control of multiple cellular processes that are crucial to endochondral ossification/OA.

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Funding

RVC Mellon Fund 5340; HEIF 6237

UK Medical Research Council funding MR/V033506/1; Department of Orthopaedics of the Royal Academy of Engineering CiET 1819/10; the Chan Zuckerberg Initiative Foundation CZIF2021-006424 and CZIF2022-316777 which contributed to data in figure 5h

Cancer Research UK (grant numbers C309/A11566 and C2739/A22897) and Merck KGaA (CrossRef Funder ID: 10.13039/100009945) which contributed to data in figure 2c and supplementary figure 8

MRC Functional Genomics Cluster and the Leducq Epigenetics of Atherosclerosis Network (LEAN) program grant from the Leducq Foundation for the curation of the epigenetic library used in supplementary figure 1

UK Medical Research Council funding (BioGrOA: Imaging joint biomechanics in growth and osteoarthritis: MR/V033506/1) which contributed to data in figure 5h

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