p21 deficiency is susceptible to osteoarthritis through STAT3 phosphorylation.

Abstract

INTRODUCTION:

Osteoarthritis (OA) is a multifactorial disease, and recent studies have suggested that cell cycle-related proteins play a role in OA pathology. p21 was initially identified as a potent inhibitor of cell cycle progression. However, it has been proposed that p21 is a regulator of transcription factor activity. In this study, we evaluated the role of p21 in response to biomechanical stress.

METHODS:

Human chondrocytes were treated with p21-specific small interfering RNA (siRNA), and cyclic tensile strain was introduced in the presence or absence of a signal transducer and activator of transcription 3 (STAT3)-specific inhibitor. Further, we developed an in vivo OA model in a p21-knockout background for in vivo experiments.

RESULTS:

The expression of matrix metalloproteinase (MMP13) mRNA increased in response to cyclic tensile strain following transfection with p21 siRNA, whereas the expression of aggrecan was decreased. Phospho-STAT3 and MMP-13 protein levels increased following downregulation of p21, and this was reversed by treatment with a STAT3 inhibitor. p21-deficient mice were susceptible to OA, and this was associated with increased STAT3 phosphorylation, elevated MMP-13 expression, and elevation of synovial inflammation. The expression of p21 mRNA was decreased and phosphorylation of STAT3 was elevated in human OA chondrocytes.

CONCLUSIONS:

The lack of p21 has catabolic effects by regulation of aggrecan and MMP-13 expression through STAT3 phosphorylation in the cartilage tissue. p21 may function as a regulator of transcriptional factors other than the inhibitor of cell cycle progression in the cartilage tissue. Thus, the regulation of p21 may be a therapeutic strategy for the treatment of OA.

• Authors: Shinya Hayashi, Takaaki Fujishiro, Shingo Hashimoto, Noriyuki Kanzaki, Nobuaki Chinzei, Shinsuke Kihara, Koji Takayama, Tomoyuki Matsumoto, Kotaro Nishida, Masahiro Kurosaka, Ryosuke Kuroda
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 17 Pg. 314 (Nov 07 2015) ISSN: 1478-6362 [Electronic] England
• PMID: 26546411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• p21-Activated Kinases

Topics

• Animals
• Blotting, Western
• Cartilage, Articular (metabolism)
• Chondrocytes
• Gene Expression Regulation (physiology)
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteoarthritis (metabolism)
• Phosphorylation
• Polymerase Chain Reaction
• RNA, Small Interfering
• STAT3 Transcription Factor (metabolism)
• Stress, Mechanical
• Transfection
• p21-Activated Kinases (metabolism)