Cyclin-Dependent Kinase Inhibitor-1-Deficient Mice are Susceptible to Osteoarthritis Associated with Enhanced Inflammation.

Abstract

Osteoarthritis (OA) is a multifactorial disease, and recent data suggested that cell cycle-related proteins play a role in OA pathology. Cyclin-dependent kinase (CDK) inhibitor 1 (p21) regulates activation of other CDKs, and recently, we reported that p21 deficiency induced susceptibility to OA induced by destabilization of the medial meniscus (DMM) surgery through STAT3-signaling activation. However, the mechanisms associated with why p21 deficiency led to susceptibility to OA by the STAT3 pathway remain unknown. Therefore, we focused on joint inflammation to determine the mechanisms associated with p21 function during in vitro and in vivo OA progression. p21-knockout (p21-/- ) mice were used to develop an in vivo OA model, and C57BL/6 (p21+/+ ) mice with the same background as the p21-/- mice were used as controls. Morphogenic changes were measured using micro-CT, IL-1β serum levels were detected by ELISA, and histological or immunohistological analyses were performed. Our results indicated that p21-deficient DMM-model mice exhibited significant subchondral bone destruction and cartilage degradation compared with wild-type mice. Immunohistochemistry results revealed p21-/- mice susceptibility to OA changes accompanied by macrophage infiltration and enhanced MMP-3 and MMP-13 expression through IL-1β-induced NF-κB signaling. p21-/- mice also showed subchondral bone destruction according to micro-CT analysis, and cathepsin K staining revealed increased numbers of osteoclasts. Furthermore, p21-/- mice displayed increased serum IL-1β levels, and isolated chondrocytes from p21-/- mice indicated elevated MMP-3 and MMP-13 expression with phosphorylation of IκB kinase complex in response to IL-1β stimulation, whereas treatment with a specific p-IκB kinase inhibitor attenuated MMP-3 and MMP-13 expression. Our results indicated that p21-deficient DMM mice were susceptible to alterations in OA phenotype, including enhanced osteoclast expression, macrophage infiltration, and MMP expression through IL-1β-induced NF-κB signaling, suggesting that p21 regulation may constitute a possible therapeutic strategy for OA treatment. © 2017 American Society for Bone and Mineral Research.

• Authors: Shinsuke Kihara, Shinya Hayashi, Shingo Hashimoto, Noriyuki Kanzaki, Koji Takayama, Tomoyuki Matsumoto, Nobuaki Chinzei, Kenjiro Iwasa, Masahiko Haneda, Kazuhiro Takeuchi, Kotaro Nishida, Ryosuke Kuroda
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 32 Issue 5 Pg. 991-1001 (May 2017) ISSN: 1523-4681 [Electronic] United States
• PMID: 28128866 (Publication Type: Journal Article)
• Copyright: © 2017 American Society for Bone and Mineral Research.

Chemical References

• Cdkn1a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p21
• IL1B protein, mouse
• Interleukin-1beta
• Matrix Metalloproteinase 13
• Mmp13 protein, mouse
• Matrix Metalloproteinase 3
• Mmp3 protein, mouse

Topics

• Animals
• Cyclin-Dependent Kinase Inhibitor p21 (deficiency)
• Disease Models, Animal
• Genetic Predisposition to Disease
• Inflammation (genetics, metabolism, pathology)
• Interleukin-1beta (genetics, metabolism)
• Matrix Metalloproteinase 13 (biosynthesis, genetics)
• Matrix Metalloproteinase 3 (biosynthesis, genetics)
• Mice
• Mice, Knockout
• Osteoarthritis (diagnostic imaging, genetics, metabolism, pathology)
• Signal Transduction
• X-Ray Microtomography