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Protein phosphatase PPM1A inhibition attenuates osteoarthritis via regulating TGF-β/Smad2 signaling in chondrocytes
Qinwen Ge, … , Peijian Tong, Hongting Jin
Qinwen Ge, … , Peijian Tong, Hongting Jin
Published February 8, 2023
Citation Information: JCI Insight. 2023;8(3):e166688. https://doi.org/10.1172/jci.insight.166688.
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Research Article Bone biology Therapeutics

Protein phosphatase PPM1A inhibition attenuates osteoarthritis via regulating TGF-β/Smad2 signaling in chondrocytes

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Abstract

TGF-β signaling is crucial for modulating osteoarthritis (OA), and protein phosphatase magnesium–dependent 1A (PPM1A) has been reported as a phosphatase of SMAD2 and regulates TGF-β signaling, while the role of PPM1A in cartilage homeostasis and OA development remains largely unexplored. In this study, we found increased PPM1A expression in OA chondrocytes and confirmed the interaction between PPM1A and phospho-SMAD2 (p-SMAD2). Importantly, our data show that PPM1A KO substantially protected mice treated with destabilization of medial meniscus (DMM) surgery against cartilage degeneration and subchondral sclerosis. Additionally, PPM1A ablation reduced the cartilage catabolism and cell apoptosis after the DMM operation. Moreover, p-SMAD2 expression in chondrocytes from KO mice was higher than that in WT controls with DMM induction. However, intraarticular injection with SD-208, repressing TGF-β/SMAD2 signaling, dramatically abolished protective phenotypes in PPM1A-KO mice. Finally, a specific pharmacologic PPM1A inhibitor, Sanguinarine chloride (SC) or BC-21, was able to ameliorate OA severity in C57BL/6J mice. In summary, our study identified PPM1A as a pivotal regulator of cartilage homeostasis and demonstrated that PPM1A inhibition attenuates OA progression via regulating TGF-β/SMAD2 signaling in chondrocytes and provided PPM1A as a potential target for OA treatment.

Authors

Qinwen Ge, Zhenyu Shi, Kai-ao Zou, Jun Ying, Jiali Chen, Wenhua Yuan, Weidong Wang, Luwei Xiao, Xia Lin, Di Chen, Xin-Hua Feng, Ping-er Wang, Peijian Tong, Hongting Jin

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Figure 1

The expression of PPM1A is involved in human OA cartilage.

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The expression of PPM1A is involved in human OA cartilage.
(A) Human car...
(A) Human cartilage samples in the tibial plateau were obtained from patients with OA who received TKA surgery. Dashed boxes indicate representative areas of intact cartilage (n = 5 individuals) and degenerated cartilage (n = 8 individuals). Scale bar: 2 cm. (B) Representative images of ABH/OG staining for intact and degenerated cartilage. Scale bar: 200 μm. (C) Representative immunofluorescent staining for Col2a1 (green) of intact and degenerated cartilage, respectively, and DAPI (blue) was used to stain nuclei. Scale bar: 50 μm. (D) The degree of cartilage degradation is quantified according to the OARSI grade. (E) Representative IHC staining for p-SMAD2. Red arrowheads indicate positive cells. Scale bar: 25 μm. (F) Quantification of p-SMAD2 positive chondrocytes ratio in human cartilage. (G) Representative IHC staining for PPM1A. Red arrows indicate positive cells. Scale bar: 50 μm. (H) Quantification of PPM1A positive cells in human cartilage. Data were presented as means ± SD and **P < 0.01 by 2-tailed unpaired parametric Student’s t test or nonparametric Mann-Whitney U test.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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