Asporin regulated by miR-26b-5p mediates chondrocyte senescence and exacerbates osteoarthritis progression via TGF-β1/Smad2 pathway

Liu, Liangliang; Zhao, Chang; Zhang, Haiyan; Lu, Yuheng; Luo, Bingsheng; Yao, Zihao; Shao, Yan; Zeng, Hua; Zeng, Chun; Zhang, Rongkai; Fang, Hang; Pan, Jinhe; Bai, Xiaochun; Cai, Daozhang

doi:10.1093/rheumatology/keab725

Cited by 21 publications

(17 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our study, the immunostaining clearly demonstrated the high level of γH2AX in cartilage from DMM animals. Previous studies have shown that the level of γH2AX was increased in both DMM mice model and cartilage explants under irradiation and mitogenic stimulation 11,35 . These results together confirmed the presence of DNA damage in OA chondrocytes.…”

Section: Discussionsupporting

confidence: 81%

In vitro study to identify ligand‐independent function of estrogen receptor‐α in suppressing DNA damage‐induced chondrocyte senescence

et al. 2023

View full text Add to dashboard Cite

In osteoarthritis (OA), chondrocytes undergo many pathological alternations that are linked with cellular senescence. However, the exact pathways that lead to the generation of a senescence‐like phenotype in OA chondrocytes are not clear. Previously, we found that loss of estrogen receptor‐α (ERα) was associated with an increased senescence level in human chondrocytes. Since DNA damage is a common cause of cellular senescence, we aimed to study the relationship among ERα levels, DNA damage, and senescence in chondrocytes. We first examined the levels of ERα, representative markers of DNA damage and senescence in normal and OA cartilage harvested from male and female human donors, as well as from male mice. The influence of DNA damage on ERα levels was studied by treating human chondrocytes with doxorubicin (DOX), which is an often‐used DNA‐damaging agent. Next, we tested the potential of overexpressing ERα in reducing DNA damage and senescence levels. Lastly, we explored the interaction between ERα and nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) pathway. Results indicated that the OA chondrocytes contained DNA damage and displayed senescence features, which were accompanied by significantly reduced ERα levels. Overexpression of ERα reduced the levels of DNA damage and senescence in DOX‐treated normal chondrocytes and OA chondrocytes. Moreover, DOX‐induced the activation of NF‐κB pathway, which was partially reversed by overexpressing ERα. Taken together, our results demonstrated the critical role of ERα in maintaining the health of chondrocytes by inhibiting DNA damage and senescence. This study also suggests that maintaining the ERα level may represent a new avenue to prevent and treat OA.

show abstract

Section: Discussionsupporting

confidence: 81%

In vitro study to identify ligand‐independent function of estrogen receptor‐α in suppressing DNA damage‐induced chondrocyte senescence

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Our previous research has clarified that KO of MMP13 or Adamts5 gene in chondrocytes could significantly alleviate the OA-like phenotypes caused by the loss of TGF-β signaling, which concluded that both MMP-13 and Adamts-5 are critical downstream targets involved in TGF-β signaling pathways during cartilage homeostasis ( 10 , 35 ). In contrast, upregulation of TGF-β signaling in chondrocytes is able to suppress the production of MMP-13 and Adamts-5, which also functions as matrix-degrading enzymes ( 36 , 37 ). According to our data, with OA induction, the rates of chondrocytes positive for MMP-13 and Adamts-5 in KO mice were significantly lower than those in WT mice.…”

Section: Discussionmentioning

confidence: 98%

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

Ge¹,

Shi²,

Zou³

et al. 2023

JCI Insight

View full text Add to dashboard Cite

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.

show abstract

“…Another study showed that the decreased expression of miR-26b-5p during the pathogenesis of OA promoted the expression of Asporin. Asporin further regulated chondrocyte senescence and in destabilization of the medial meniscus (DDM)-induced joint degeneration by inhibiting the TGF-β1/Smad2 signaling pathway [ 45 ]. Although it has been confirmed that cartilage aging and OA progression are closely related to knee joint degeneration or osteoarthritis, it is rarely reported whether chondrocyte senescence is related to degeneration progression during facet joint degeneration.…”

Section: Discussionmentioning

confidence: 99%

Mechanical overloading-induced miR-325-3p reduction promoted chondrocyte senescence and exacerbated facet joint degeneration

et al. 2023

View full text Add to dashboard Cite

Objective Lumbar facet joint (LFJ) degeneration is one of the main causes of low back pain (LBP). Mechanical stress leads to the exacerbation of LFJ degeneration, but the underlying mechanism remains unknown. This study was intended to investigate the mechanism of LFJ degeneration induced by mechanical stress. Methods Here, mice primary chondrocytes were used to screen for key microRNAs induced by mechanical overloading. SA-β-gal staining, qRT-PCR, western blot, and histochemical staining were applied to detect chondrocyte senescence in vitro and in vivo. We also used a dual-luciferase report assay to examine the targeting relationship of miRNA-325-3p (miR-325-3p) and Trp53. By using NSC-207895, a p53 activator, we investigated whether miR-325-3p down-regulated trp53 expression to reduce chondrocyte senescence. A mice bipedal standing model was performed to induce LFJ osteoarthritis. Adeno-associated virus (AAV) was intraarticularly injected to evaluate the effect of miR-325-3p on facet joint degeneration. Results We observed chondrocyte senescence both in human LFJ osteoarthritis tissues and mice LFJ after bipedally standing for 10 weeks. Mechanical overloading could promote chondrocyte senescence and senescence-associated secretory phenotype (SASP) expression. MicroRNA-array analysis identified that miR-325-3p was obviously decreased after mechanical overloading, which was further validated by fluorescence in situ hybridization (FISH) in vivo. Dual-luciferase report assay showed that miR-325-3p directly targeted Trp53 to down-regulated its expression. MiR-325-3p rescued chondrocyte senescence in vitro, however, NSC-207895 reduced this effect by activating the p53/p21 pathway. Intraarticular injection of AAV expressing miR-325-3p decreased chondrocyte senescence and alleviated LFJ degeneration in vivo. Conclusion Our findings suggested that mechanical overloading could reduce the expression of miR-325-3p, which in turn activated the p53/p21 pathway to promote chondrocyte senescence and deteriorated LFJ degeneration, which may provide a promising therapeutic strategy for LFJ degeneration.

show abstract

Asporin regulated by miR-26b-5p mediates chondrocyte senescence and exacerbates osteoarthritis progression via TGF-β1/Smad2 pathway

Cited by 21 publications

References 36 publications

In vitro study to identify ligand‐independent function of estrogen receptor‐α in suppressing DNA damage‐induced chondrocyte senescence

In vitro study to identify ligand‐independent function of estrogen receptor‐α in suppressing DNA damage‐induced chondrocyte senescence

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

Mechanical overloading-induced miR-325-3p reduction promoted chondrocyte senescence and exacerbated facet joint degeneration

Contact Info

Product

Resources

About