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

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.

Benzophenanthridine Alkaloid Chelerythrine Elicits Necroptosis of Gastric Cancer Cells via Selective Conjugation at the Redox Hyperreactive C-Terminal Sec498 Residue of Cytosolic Selenoprotein Thioredoxin Reductase

“…Notably, the results showed that the growth of NCI-N87-derived spheroids was significantly inhibited, indicating the therapeutic potential of chelerythrine and sanguinarine in chemotherapy. Furthermore, the cellular effects of chelerythrine and sanguinarine were recently investigated in vivo [66,68,69]. The results suggest that chelerythrine, as well as sanguinarine, is a potential candidate for cancer chemotherapy and other diseases.…”

Protein phosphatases regulate the formation of Müller glia-derived progenitor cells in the chick retina

“…In addition, PPM1B dephosphorylates IKKβ to terminate TNFα-induced NFkB activation [78], and inhibition of NFkB is known to stimulate the proliferation of MGPCs [35]. Sanguinarine is also known to inhibit PPM1A which is known to deactivate pSMAD2/3 [52, 79]; SMAD3-signaling is known to suppress the formation of MGPCs in the chick retina [29]. Thus, inhibition of PPM1A by sanguinarine might be expected to increase MGPC proliferation by suppressing SMAD3- and NFkB-signaling.…”