TY - JOUR
T1 - Epigenetic dysregulation of articular cartilage during progression of hip femoroacetabular impingement disease
AU - Kamenaga, Tomoyuki
AU - Shen, Jie
AU - Wu, May
AU - Brophy, Robert H.
AU - Clohisy, John C.
AU - O'Keefe, Regis J.
AU - Pascual-Garrido, Cecilia
N1 - Funding Information:
The authors would like to thank Crystal Idleburg and Samantha Coleman for their technical assistance and Chadi Nahal, Gail E. Pashos, Sean M. Akers, Caroline Drain, and Karla J. Crook for their assistance. This study was supported in part by the NIH KO8 Clinical Investigator Award, 1K08AR077740‐01, NIH R01 award, R01AR069605, 0REF/Goldberg Research Grant in Arthritis and the OREF Mentored Clinician Scientist Grant. Curing Hip Disease Fund and Jackie and Randy Baker Research Funds provided partial support for the research personnel.
Publisher Copyright:
© 2023 Orthopaedic Research Society. Published by Wiley Periodicals LLC.
PY - 2023
Y1 - 2023
N2 - Femoroacetabular impingement (FAI) is an important trigger of hip osteoarthritis (OA). Epigenetic changes in DNA methyltransferase 3B (DNMT3B) attenuate catabolic gene expression in cartilage hemostasis. This study aimed to examine the articular chondrocyte catabolic state and DNMT3B and 4-aminobutyrate aminotransferase promoter (ABAT) expression during OA progression in FAI. Cartilage samples were collected from the impingement zone of 12 patients with cam FAI (early-FAI) and 12 patients with advanced OA secondary to cam FAI (late-FAI-OA). Five healthy samples were procured from cadavers (ND: nondiseased). Explants were cultured under unstimulated conditions, catabolic stimulus (IL1β), or anabolic stimulus (TGFβ). Histology was performed with safranin-O/fast-green staining. Gene expression was analyzed via qPCR for GAPDH, DNMT3B, ABAT, MMP-13, COL10A1. Methylation specific PCR assessed methylation status at the ABAT promoter. Cartilage samples in early-FAI and late-FAI-OA showed a histological OA phenotype and increased catabolic marker expression (MMP13/COL10A1, ND vs. early-FAI, p = 0.004/p < 0.001, ND vs. late-FAI-OA, p < 0.001/p < 0.001). RT-PCR confirmed DNMT3B underexpression (ND vs. early-FAI, p < 0.001, early-FAI vs. late-FAI-OA, p = 0.016) and ABAT overexpression (ND vs. early-FAI, p < 0.001, early vs. late-FAI-OA, p = 0.035) with advanced disease. End-stage disease showed ABAT promoter hypomethylation. IL1β stimulus accentuated ABAT promoter hypomethylation and led to further ABAT and catabolic marker overexpression in early-FAI and late-FAI-OA while TGFβ normalized these alterations in gene expression. Catabolic and epigenetic molecule expression suggested less catabolism in early-stage disease. Sustained inflammation induced ABAT promoter hypo-methylation causing a catabolic phenotype. Suppression of ABAT by methylation control could be a new target for therapeutic intervention to prevent OA progression in hip FAI.
AB - Femoroacetabular impingement (FAI) is an important trigger of hip osteoarthritis (OA). Epigenetic changes in DNA methyltransferase 3B (DNMT3B) attenuate catabolic gene expression in cartilage hemostasis. This study aimed to examine the articular chondrocyte catabolic state and DNMT3B and 4-aminobutyrate aminotransferase promoter (ABAT) expression during OA progression in FAI. Cartilage samples were collected from the impingement zone of 12 patients with cam FAI (early-FAI) and 12 patients with advanced OA secondary to cam FAI (late-FAI-OA). Five healthy samples were procured from cadavers (ND: nondiseased). Explants were cultured under unstimulated conditions, catabolic stimulus (IL1β), or anabolic stimulus (TGFβ). Histology was performed with safranin-O/fast-green staining. Gene expression was analyzed via qPCR for GAPDH, DNMT3B, ABAT, MMP-13, COL10A1. Methylation specific PCR assessed methylation status at the ABAT promoter. Cartilage samples in early-FAI and late-FAI-OA showed a histological OA phenotype and increased catabolic marker expression (MMP13/COL10A1, ND vs. early-FAI, p = 0.004/p < 0.001, ND vs. late-FAI-OA, p < 0.001/p < 0.001). RT-PCR confirmed DNMT3B underexpression (ND vs. early-FAI, p < 0.001, early-FAI vs. late-FAI-OA, p = 0.016) and ABAT overexpression (ND vs. early-FAI, p < 0.001, early vs. late-FAI-OA, p = 0.035) with advanced disease. End-stage disease showed ABAT promoter hypomethylation. IL1β stimulus accentuated ABAT promoter hypomethylation and led to further ABAT and catabolic marker overexpression in early-FAI and late-FAI-OA while TGFβ normalized these alterations in gene expression. Catabolic and epigenetic molecule expression suggested less catabolism in early-stage disease. Sustained inflammation induced ABAT promoter hypo-methylation causing a catabolic phenotype. Suppression of ABAT by methylation control could be a new target for therapeutic intervention to prevent OA progression in hip FAI.
KW - DNA methylation
KW - articular cartilage
KW - epigenetic
KW - femoroacetabular impingement
KW - hip osteoarthritis
UR - http://www.scopus.com/inward/record.url?scp=85146358684&partnerID=8YFLogxK
U2 - 10.1002/jor.25513
DO - 10.1002/jor.25513
M3 - Article
C2 - 36606425
AN - SCOPUS:85146358684
SN - 0736-0266
JO - Journal of Orthopaedic Research
JF - Journal of Orthopaedic Research
ER -