Background/Purpose:

Osteoarthritis (OA) was once viewed as a mechanical disease of “wear and tear”, but recent advances suggest that OA results from active dysregulation of chondrocyte biology leading to catabolism of the cartilage matrix. Little is understood regarding the transcription factors that regulate this catabolic program and ultimately the development of OA. Nuclear factor of activated T cells (NFATs) are a family of transcription factors with broad roles in vertebrate physiology including immune responses and tissue development. Since NFAT family members often display redundant functions and NFATc2-deficient mice were previously shown to develop OA at older ages, we tested the role of NFATc1 in OA.

Methods:

Mice bearing two copies of a floxed allele of Nfatc1 (Nfatc1^fl/fl) were crossed  to Col2-cre mice to delete the gene in cartilage (Nfatc1^col2 mice). Nfatc1^col2 mice were analyzed in the destabilization of the medial meniscus (DMM) model of OA. The Nfatc1^col2 strain was bred onto the NFATc2-deficient background to generate Nfatc1^col2Nfatc2^-/- mice. These mice were analyzed by microCT, immunohistochemistry and quantitative real-time PCR (qPCR) of mRNA isolated from dissected cartilage tissue. mRNA purified from human cartilage tissue from joint replacement surgery was also interrogated for NFATC1 and NFATC2 expression by qPCR.

Results:

NFATc1^col2 mice were not more susceptible to OA in the DMM model than littermate controls, suggesting that in mice, NFATc1 deficiency is not sufficient to accelerate OA. In contrast, cartilage-specific ablation of Nfatc1 in Nfatc2^-/- mice led to a spontaneous, early onset, aggressive OA. The arthritis affects multiple joints including the knees, elbows and tarsal-metatarsal joints and is associated with subluxations. Histologically, joints from Nfatc1^col2Nfatc2^-/- mice showed loss of proteoglycans, increases in collagen and aggrecan degradation products and eventual progression to cartilage effacement. MicroCT demonstrated increased osteophyte formation and changes to the subchondral bone in Nfatc1^col2Nfatc2^-/- mice. Compared with littermate controls, cartilage dissected from the knee joints of Nfatc1^col2Nfatc2^-/- mice showed increased expression of: Mmp13, Adamts5, Col2a1 and Htra1. Lastly, NFATC1 expression is downregulated in paired lesional versus macroscopically normal cartilage samples from OA patients (1.63 vs. 2.72, p=0.0065 by paired t-test). No significant change was observed in NFATC2 expression (2.44 vs. 2.06, p=0.214).

Conclusion:

NFATs are suppressors of OA and regulating NFATs or their transcriptional targets in chondrocytes may lead to novel disease modifying OA therapies. The Nfatc1^col2Nfatc2^-/- mice have a highly penetrant, early onset and severe OA phenotype, which could be an attractive platform for the preclinical development of treatments to alter the course of this disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/spontaneous-osteoarthritis-in-mice-by-genetic-deletion-of-nfatc1-and-nfatc2/