Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1^Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1^Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1^Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

压电蛋白是机械激活的离子通道，是多种细胞类型的机械传感功能所必需的。虽然我们和其他人之前已经证明Piezo1在成骨细胞谱系细胞中的表达对于骨合成代谢过程至关重要，但只有暗示性证据表明 Piezo1 和/或 Piezo2 在软骨中的作用。在这里，我们解决了软骨细胞表达机械敏感蛋白 Piezo1 或 Piezo2 是否以及如何控制生理性软骨内骨化和病理性骨关节炎 (OA) 发展的问题。软骨细胞特异性失活 Piezo1 ( Piezo1 ^Col2a1Cre ) 而不是 Piezo2 的小鼠，出生后软骨生长板下方几乎没有骨小梁。此外，所有Piezo1 ^Col2a1Cre动物在 7 日龄时均表现出多处肋骨骨折，这些骨折位于靠近生长板的位置。虽然这些小鼠的骨骼生长仅受到轻微影响，但与 60 周龄的同窝对照小鼠相比，OA 病理明显不那么明显。同样，当通过前交叉韧带横断诱导 OA 时，只有 Piezo1 而非 Piezo2 的软骨细胞失活导致关节软骨退化减弱。重要的是， Piezo1 ^Col2a1Cre小鼠中骨赘的形成和成熟也有所减少。我们进一步观察到人类骨赘软骨区中 Piezo1 蛋白丰度增加。最后，我们将Ptgs2和Ccn2确定为软骨细胞中潜在相关的 Piezo1 下游基因。总的来说，我们的数据不仅证明 Piezo1 是生理和病理性软骨内骨化过程的关键调节剂，而且表明 Piezo1 拮抗剂可能被确立为限制 OA 骨赘形成的新方法。