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Mocetinostat activates Kruppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis

ABSTRACT: Kruppel-like factor-4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissue cells. To explore novel therapeutic candidates for osteoarthritis (OA), high-throughput screening (HTS) with 11,948 compounds was per-formed using a reporter cell line detecting endogenous KLF4 activation. Eighteen com-pounds were identified through the HTS and confirmed in a secondary screen. Among them, mocetinostat, a class I histone deacetylase inhibitor, had the best biological activi-ties. Mocetinostat upregulated chondrogenic genes in human chondrocytes, meniscal cells, and mesenchymal stem cells, while it down-regulated hypertrophic, inflammatory and cat-abolic genes in those cells and synoviocytes. Intraperitoneal administration of mocetino-stat into mice reduced severity of OA-associated changes in cartilage, meniscus and syno-vium and improved pain behaviors. Global gene expression and proteomics analyses re-vealed that regenerative and protective effects of mocetinostat depended on peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These findings qualify mocetino-stat as a potential candidate for disease modifying OA drugs.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Martin K Lotz, MD

PROVIDER: MSV000091049 | MassIVE | Wed Jan 11 16:20:00 GMT 2023

SECONDARY ACCESSION(S): PXD039364

REPOSITORIES: MassIVE

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Project description:Autologous chondrocyte transplantation (ACT) is a routine technique to regenerate focal cartilage lesions. However, patients with osteoarthritis (OA) are lacking an appropriate long-lasting treatment alternative, partly since it is not known if chondrocytes from OA patients have the same chondrogenic differentiation potential as chondrocytes from donors not affected by OA. Articular chondrocytes from patients with OA undergoing total knee replacement (Mankin Score >3, Ahlbäck Score >2) and from patients undergoing ACT, here referred to as normal donors (ND), were isolated applying protocols used for ACT. Their chondrogenic differentiation potential was evaluated both in high-density pellet and scaffold (Hyaff-11) cultures by histological proteoglycan assessment (Bern Score) and immunohistochemistry for collagen types I and II. Chondrocytes cultured in monolayer and scaffolds were subjected to gene expression profiling using genome-wide oligonucleotide microarrays. Expression data were verified by using quantitative RT-PCR. Chondrocytes from ND and OA donors demonstrated accumulation of comparable amounts of cartilage matrix components, including sulphated proteoglycans and collagen types I and II. The mRNA expression of cartilage markers (COL2A1, COMP, aggrecan, CRTL1, SOX9) and genes involved in matrix synthesis (biglycan, COL9A2, COL11A1, TIMP4, CILP2) was highly induced in 3D cultures of chondrocytes from both donor groups. Genes associated with hypertrophic or OA cartilage (COL10A1, RUNX2, periostin, ALP, PTHR1, MMP13, COL1A1, COL3A1) were not significantly regulated between the two groups of donors. The expression of 661 genes, including COMP, FN1, and SOX9, were differentially regulated between OA and ND chondrocytes cultured in monolayer. During scaffold culture, the differences diminished between the OA and ND chondrocytes, and only 184 genes were differentially regulated. Only few genes were differentially expressed between OA and ND chondrocytes in Hyaff-11 culture. The risk of differentiation into hypertrophic cartilage does not seem to be increased for OA chondrocytes. Our findings suggest that the chondrogenic capacity is not significantly affected by OA and OA chondrocytes fulfill the requirements for matrix-associated ACT. Keywords: time course, cell type comparison, tissue engineered cartilage; osteoarthritis; Hyaff-11 scaffold; human chondrocytes; gene expression profiling; regenerative medicine; differentiation potential

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Mocetinostat activates Kruppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis

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