Ely Erica V, Lenz Kristin L, Paradi Sophie G, Ack Seth, Behrmann Abraham, Dunivan Sarah, Braxton Lauryn, Liedtke Wolfgang, Chen Yong, Collins Kelsey H, Guilak Farshid
Department of Orthopaedic Surgery, Washington University in Saint Louis, Missouri, Saint Louis, 63110, USA.
Shriners Hospitals for Children-St. Louis, St. Louis, Missouri, USA.
Arthritis Res Ther. 2025 Jul 19;27(1):152. doi: 10.1186/s13075-025-03620-w.
Osteoarthritis (OA) is a debilitating joint disease characterized by cartilage degeneration, synovial inflammation, and bone remodeling, with limited therapeutic options targeting the underlying pathophysiology. Mechanosensitive ion channels Piezo1 and Piezo2 play crucial roles in chondrocyte responses to mechanical stress, mediating mechanotransduction pathways that influence chondrocyte survival, matrix production, and inflammatory signaling, but their distinct contributions to OA pathogenesis remain unclear.
Using inducible, chondrocyte-specific Aggrecan-Cre (Acan) mice, we investigated Piezo1, Piezo2, and combined Piezo1/2 conditional knockouts (cKOs) using the destabilization of the medial meniscus (DMM) model of post-traumatic OA in male and female mice. Pain and behavioral assessments were conducted at four time points to evaluate OA progression, while cartilage damage, bone remodeling, and synovial inflammation were assessed at the final endpoint of 28 weeks. Statistical analyses included one-way and two-way ANOVA with Tukey's multiple comparison test.
Piezo1 cKO delayed pain onset but ultimately exacerbated cartilage degradation and synovitis, emphasizing its dual role in protective and pathogenic mechanotransduction. While the Piezo2 cKO reduced pain and preserved activity, it failed to protect cartilage. Notably, Piezo1/2 cKO provided the greatest protection against cartilage degeneration, synovitis, and pain. Micro-computed tomography analyses revealed that Piezo2 is critical for maintaining trabecular bone integrity, with a Piezo2 cKO leading to decreased bone volume, thickness, and density, independent of injury. Piezo2 cKO also reduced normal meniscal ossification that occurs with age in mice. In contrast, a Piezo1/2 cKO normalized most bone remodeling parameters observed in Piezo2 cKO mice but did not restore medial tibial plateau thickness, highlighting Piezo2's essential role in bone structure.
These findings demonstrate the overlapping and compensatory roles of Piezo1 and Piezo2 in OA pathogenesis. Dual inhibition of Piezo1 and Piezo2 may offer a novel, effective therapeutic strategy targeting both structural and symptomatic aspects of the disease.
骨关节炎（OA）是一种使人衰弱的关节疾病，其特征为软骨退变、滑膜炎症和骨重塑，针对潜在病理生理学的治疗选择有限。机械敏感离子通道Piezo1和Piezo2在软骨细胞对机械应力的反应中起关键作用，介导影响软骨细胞存活、基质产生和炎症信号传导的机械转导途径，但其对OA发病机制的不同贡献仍不清楚。
使用诱导性软骨细胞特异性聚集蛋白聚糖-Cre（Acan）小鼠，我们在雄性和雌性小鼠的创伤后OA内侧半月板不稳定（DMM）模型中研究了Piezo1、Piezo2以及联合的Piezo1/2条件性敲除（cKO）。在四个时间点进行疼痛和行为评估以评估OA进展，而在28周的最终终点评估软骨损伤、骨重塑和滑膜炎。统计分析包括单向和双向方差分析以及Tukey多重比较检验。
Piezo1 cKO延迟了疼痛发作，但最终加剧了软骨降解和滑膜炎，强调了其在保护性和致病性机械转导中的双重作用。虽然Piezo2 cKO减轻了疼痛并保持了活动能力，但未能保护软骨。值得注意的是，Piezo1/2 cKO对软骨退变、滑膜炎和疼痛提供了最大程度的保护。微型计算机断层扫描分析显示，Piezo2对维持小梁骨完整性至关重要，Piezo2 cKO导致骨体积、厚度和密度降低，与损伤无关。Piezo2 cKO还减少了小鼠随年龄增长而发生的正常半月板骨化。相比之下，Piezo1/2 cKO使Piezoe2 cKO小鼠中观察到的大多数骨重塑参数正常化，但未恢复内侧胫骨平台厚度，突出了Piezo2在骨结构中的重要作用。
这些发现证明了Piezo1和Piezo2在OA发病机制中的重叠和补偿作用。对Piezo1和Piezo2的双重抑制可能提供一种针对该疾病结构和症状方面的新型有效治疗策略。
