Editorial: The role of Piezo 1 in osteoarthritis: Implications for pathogenesis and therapy

Osteoarthritis (OA) is a leading cause of disability, characterized by progressive cartilage degradation, inflammation, and pain. This editorial examines the role of the mechanosensitive ion channel Piezo 1 in OA pathogenesis and its potential as a therapeutic target.

Osteoarthritis affects millions worldwide, presenting with joint pain, stiffness, and reduced mobility.^{1, 2} The disease's complexity involves mechanical stress, genetic predisposition, and inflammatory processes. Piezo 1, a mechanosensitive ion channel, has gained attention for its role in transducing mechanical stimuli into cellular responses that exacerbate joint degradation.^{3, 4}

Piezo 1 channels are essential for chondrocytes to sense and respond to mechanical loads.^{3, 5} Normally, these channels help maintain cartilage homeostasis by regulating matrix synthesis and chondrocyte proliferation.⁶ In OA, however, abnormal mechanical loading or inflammatory cytokines such as IL-1β can over-activate Piezo 1, leading to increased catabolic activity and apoptosis, thus accelerating cartilage erosion.^7-9

Excessive activation of Piezo 1 in OA can initiate a cascade of degenerative processes in the joint. Piezo 1 mediates the upregulation of matrix metalloproteinases (MMPs) and aggrecanases, which degrade cartilage matrix components, contributing significantly to cartilage structural breakdown.^{6, 10} Additionally, Piezo 1 activation affects inflammatory pathways, enhancing cytokine production and perpetuating a pro-inflammatory environment within the joint.^{5, 11} Another study indicates that Piezo 1 acts as a key mediator in osteoarthritis by converting mechanical stress into cellular signals that promote chondrocyte senescence, thereby accelerating the progression of the disease.¹² Figure 1 illustrates how Piezo 1 activation under mechanical load or inflammatory conditions leads to calcium ion influx, which then activates downstream pathways such as PI3K/AKT/mTOR, MAPK, and NF-κB. These pathways are critical in mediating chondrocyte senescence, matrix degradation, and inflammation, collectively driving the progression of OA.

Considering the detrimental effects of Piezo 1 overactivation in OA, targeting this channel represents a promising therapeutic strategy. Inhibiting Piezo 1 activity has been shown to reduce cartilage degradation in preclinical models, suggesting its potential to halt or even reverse OA progression.^{8, 13} Further studies exploring selective Piezo 1 inhibitors or modulators are crucial for developing drugs that can specifically target mechanotransduction pathways involved in OA.^{4, 10}

Evidence from recent studies, as summarized in Table 1, indicates that specific modulation of Piezo 1 activity can alter the disease course of OA. For instance, PI3K/AKT/mTOR is known to regulate cell survival, inflammation, and matrix production in chondrocytes.⁷ Targeting these pathways in conjunction with Piezo 1 may provide a multifaceted approach to managing OA, potentially improving therapeutic efficacy and patient outcomes.

Piezo 1 is a pivotal mechanosensitive ion channel that plays a critical role in the pathogenesis of osteoarthritis through its regulation of chondrocyte biomechanical signaling and inflammatory responses. Targeting Piezo 1 and its associated pathways offers a novel therapeutic avenue that could lead to more effective treatments for OA. Continued research is essential to translate these findings into clinical therapies that can provide relief and improved quality of life for patients suffering from this debilitating condition.

Figure 1. Role of Piezo 1 in osteoarthritis pathogenesis. This diagram illustrates the mechanotransduction mechanism of Piezo 1 in chondrocytes under mechanical stress and inflammatory conditions. Mechanical forces and inflammatory signals activate the Piezo 1 ion channel, leading to an influx of calcium ions (Ca²⁺). This calcium influx triggers downstream signaling pathways, including PI3K/AKT/mTOR, MAPK, and NF-κB, which contribute to chondrocyte senescence, matrix degradation, and inflammation. These processes collectively drive the progression of osteoarthritis (OA). The upregulation of Piezo 1 further enhances the mechanical sensitivity of chondrocytes, exacerbating OA pathogenesis.

The first author was responsible for the conceptualization, methodology and writing of the manuscript. The corresponding author provided guidance throughout the research process, contributed to the manuscript review, and ensured the integrity of the work.

This work was supported by the funding from the Shenzhen Science and Technology Innovation Commission (JCYJ2021032413181), the Shenzhen High-level Hospital Construction Fund, and the Shenzhen Third People's Hospital Project Fund (G2022063). The funding bodies had no role in the design of the study, the collection, analysis, and interpretation of data, or in writing the manuscript.

The authors declare that there are no conflicts of interest regarding the publication of this article.