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Increased WISP1 expression in human osteoarthritic articular cartilage is epigenetically regulated and decreases
Martijn H J van den Bosch1, Yolande F M Ramos2, Wouter den Hollander2
1Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
Objectives:
Previously, we have shown the involvement of Wnt-activated protein Wnt-1-induced signaling protein 1 (WISP1) in the development of OA in mice. Here, we aimed to characterize the relation between WISP1 expression and human OA and its regulatory epigenetic determinants.
Methods:
Preserved and lesioned articular cartilage from end-stage OA patients and non-OA-diagnosed individuals was collected. WISP1 expression was determined using immunohistochemistry and damage was classified using Mankin scoring. RNA expression and DNA methylation were assessed in silico from genome-wide datasets (microarray analysis and RNA sequencing, and 450 k-methylationarrays, respectively). Effects of WISP1 were tested in pellet cultures of primary human chondrocytes.
Results:
WISP1 expression in cartilage of OA patients was increased compared with non-OA-diagnosed controls and, within OA patients, WISP1 was even higher in lesioned compared with preserved regions, with expression strongly correlating with Mankin score. In early symptomatic OA patients with disease progression, higher synovial WISP1 expression was observed as compared with non-progressors. Notably, increased WISP1 expression was inversely correlated with methylation levels of a positional CpG-dinucleotide (cg10191240), with lesioned areas showing strong hypomethylation for this CpG as compared with preserved cartilage. Additionally, we observed that methylation levels were allele-dependent for an intronic single-nucleotide polymorphism nearby cg10191240. Finally, addition of recombinant WISP1 to pellets of primary chondrocytes strongly inhibited deposition of extracellular matrix as reflected by decreased pellet circumference, proteoglycan content and decreased expression of matrix components.
Conclusion:
Increased WISP1 expression is found in lesioned human articular cartilage, and appears epigenetically regulated via DNA methylation. In vitro assays suggest that increased WISP1 is detrimental for cartilage integrity.
Insights
Wnt-1-induced signaling protein 1 (WISP1) is elevated in damaged human osteoarthritis cartilage and epigenetically regulated by DNA methylation. Increased WISP1 harms cartilage integrity, suggesting it as a therapeutic target.
Area of Science:
- Biochemistry
- Epigenetics
- Osteoarthritis Research
Background:
- Wnt-1-induced signaling protein 1 (WISP1) has been implicated in mouse osteoarthritis (OA) development.
- Understanding WISP1's role in human OA and its epigenetic regulation is crucial.
Purpose of the Study:
- To characterize the relationship between WISP1 expression and human OA.
- To identify epigenetic determinants regulating WISP1 in OA.
Main Methods:
- Collected human articular cartilage from OA patients and controls.
- Assessed WISP1 expression via immunohistochemistry and Mankin scoring.
- Analyzed RNA expression and DNA methylation using in silico genome-wide datasets.
- Investigated WISP1 effects on human chondrocytes in vitro.
Main Results:
- WISP1 expression was significantly higher in OA cartilage, particularly in lesioned areas, correlating with OA severity (Mankin score).
- Elevated synovial WISP1 levels were observed in early OA patients with disease progression.
- Increased WISP1 expression inversely correlated with DNA hypomethylation at a specific CpG site (cg10191240), suggesting epigenetic regulation.
- In vitro, WISP1 addition inhibited extracellular matrix deposition in chondrocyte cultures.
Conclusions:
- Increased WISP1 expression in lesioned human OA cartilage is epigenetically regulated by DNA methylation.
- In vitro data suggest that elevated WISP1 is detrimental to cartilage integrity, highlighting its potential as a therapeutic target.
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