Krüppel-like factor 15 deficiency exacerbates osteoarthritis through reduced expression of peroxisome proliferator-activated receptor gamma signaling in mice.

Abstract

OBJECTIVE:

Krüppel-like zinc finger transcription factors (KLFs) play diverse roles in mammalian cell differentiation and development. In this study, we investigated the function of KLF15 in the progression of osteoarthritis (OA).

METHODS:

0Destabilization of the medial meniscus (DMM) surgery was performed in 10-week-old male wild-type control (WT) mice and cartilage-specific KLF15 knockout (KO) mice. Histological analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining were performed. Morphological changes were measured using microcomputed tomography. Six mice from each group were analyzed (total number of mice analyzed: 60). In vitro, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blot analyses were performed.

RESULTS:

KLF15 KO DMM mice exhibited significant cartilage degradation compared to WT mice. According to the Osteoarthritis Research Society International cartilage OA-histopathology scoring system, the mean sum score in KLF15 KO mice was significantly higher than that in WT mice at 8 weeks after surgery. Immunohistochemistry results revealed KLF15 KO mice exhibited reduced peroxisome proliferator-activated receptor gamma (PPARγ) expression, increased pIKKα/β, a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTS) 5, and Matrix metalloproteinases (MMP13) expression, and reduced Forkhead box O (FOXO1) and Light chain 3B (LC3B) expression. Inhibition of PPARγ phosphorylation accelerated the effects of interleukin (IL) 1β-treatment in both KLF15 KO and WT chondrocytes, and activation of PPARγ expression canceled the IL1β-induced catabolic effects.

CONCLUSION:

Our results indicated that the OA phenotype of KLF15 KO DMM mice was influenced by reduced PPARγ expression, including enhanced pIKKα/β, ADAMTS5, and MMP13 expression, reduced autophagy, and increased apoptosis. KLF15 regulation may constitute a possible therapeutic strategy for the treating OA.

• Authors: Kemmei Ikuta, Shinya Hayashi, Kenichi Kikuchi, Masahiro Fujita, Kensuke Anjiki, Yuma Onoi, Shotaro Tachibana, Yoshihito Suda, Kensuke Wada, Yuichi Kuroda, Naoki Nakano, Toshihisa Maeda, Tomoyuki Matsumoto, Tetsuya Hosooka, Wataru Ogawa, Ryosuke Kuroda
• Journal: Osteoarthritis and cartilage (Osteoarthritis Cartilage) Vol. 32 Issue 1 Pg. 28-40 (Jan 2024) ISSN: 1522-9653 [Electronic] England
• PMID: 37648149 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Kruppel-Like Transcription Factors
• Matrix Metalloproteinase 13
• PPAR gamma
• Klf15 protein, mouse

Topics

• Animals
• Male
• Mice
• Cartilage, Articular (pathology)
• Chondrocytes (metabolism)
• Disease Models, Animal
• Kruppel-Like Transcription Factors (genetics, metabolism, pharmacology)
• Mammals (metabolism)
• Matrix Metalloproteinase 13 (genetics, metabolism)
• Mice, Knockout
• Osteoarthritis (metabolism)
• PPAR gamma (genetics, metabolism)
• X-Ray Microtomography