Piezo1 protein induces the apoptosis of human osteoarthritis-derived chondrocytes by activating caspase-12, the signaling marker of ER stress

Abstract

The present study was carried out to determine whether the mechanically activated cation channel Piezo1 protein plays a role as a signaling pathway which causes the apoptosis of human chondrocytes. The chondrocytes were isolated, cultured, and then subjected to mechanical stretch force for 0, 2, 12, 24 and 48 h, respectively. The expression levels of Piezo1 and the apoptosis-related protein caspase-12 were assessed by reverse transcription-quantitative polymerase chain reaction, as well as the apoptosis-related genes, B cell lymphoma/leukemia-2 (Bcl-2), Bcl-associated X protein (Bax) and Bcl-2-associated death promoter (BAD). Lactate dehydrogenase (LDH) activity was used to discern dead cells. Piezo1 expression was determined by immunofluorescence. In addition, Piezo1 inhibitor, GsMTx4, was used to block the mechanically activated (MA) cation channel Piezo1, and served as a positive control. The results showed that the osteoarthritis (OA)-derived chondrocytes showed a tendency to undergo late-stage apoptosis under compressive loading. Piezo1 and caspase-12 were significantly upregulated under static compressive stimuli and the expression was related to the rate of apoptosis of the OA-derived chondrocytes during compressive loading. The expression of caspase-12 and late-stage apoptosis of the human OA-derived chondrocytes were repressed by GsMTx4, the specific inhibitor of Piezo1, while the expression of Piezo1 and the induction of the apoptosis of the OA-derived chondrocytes during compressive loading was not totally blocked. Thus, we conclude that Piezo1 plays an important role in the apoptosis of human OA-derived chondrocytes through a caspase-12-dependent pathway. The expression of Piezo1 protein was not totally inhibited by GsMTx4.

Ablation of PKM2 ameliorated ER stress‐induced apoptosis and associated inflammation response in IL‐1β‐treated chondrocytes via blocking Rspo2‐mediated Wnt/β‐catenin signaling

“…18 Mounting evidence indicates that ER stress can lead to chondrocyte apoptosis and OA progression. [19][20][21] Recent evidence also reports that physiological and pharmacological agent stimulation leads to ER stress in chondrocytes in vitro. 9 Further, ER stress-related protein GRP78 is elevated in ER stress.…”

Mechanoelectrical transduction in chondrocytes

“…This Ca 2+ signal was significantly reduced when both PIEZO1 and PIEZO2 were knocked down . More recently, the PIEZO1‐mediated accumulation of intracellular Ca 2+ in response to compressive loading has been implicated in apoptotic cell death in chondrocytes, potentially contributing to the development of OA in some individuals. This observation is supported by an additional study showing that the peptide, urocortin, can protect chondrocytes from apoptosis by blocking PIEZO1 …”

Pharmacologic Interventions for Preventing Chondrocyte Apoptosis in Rheumatoid Arthritis and Osteoarthritis

“…These included BCL-2-like protein-11 (Bim) [18], B-cell lymphoma-2 (Bcl-2) [75], cell-derived inhibitors of apoptosis proteins (IAPs) [81][82][83][84] and Suppressor of Cytokine Synthesis (SOCS) [85,86]. Furthermore, alterations in the functions of mitochondria [87] and endoplasmic reticulum (ER) [88][89][90][91] related to cell stress, the generation of reactive oxygen species [92] and the recently described advanced oxidation protein products [93] with respect to their capacity to induce apoptosis were reported as well. Taken together, these results provided compelling evidence that pro-inflammatory cytokines, growth factors and soluble mediators germane to the progression of RA and OA are responsible for inducing chondrocyte apoptosis in these conditions.…”