Kobayashi Tatsuya, Chung Ung-Il, Schipani Ernestina, Starbuck Michael, Karsenty Gerard, Katagiri Takenobu, Goad Dale L, Lanske Beate, Kronenberg Henry M
Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Development. 2002 Jun;129(12):2977-86. doi: 10.1242/dev.129.12.2977.
In developing murine growth plates, chondrocytes near the articular surface (periarticular chondrocytes) proliferate, differentiate into flat column-forming proliferating cells (columnar chondrocytes), stop dividing and finally differentiate into hypertrophic cells. Indian hedgehog (Ihh), which is predominantly expressed in prehypertrophic cells, stimulates expression of parathyroid hormone (PTH)-related peptide (PTHrP) which negatively regulates terminal chondrocyte differentiation through the PTH/PTHrP receptor (PPR). However, the roles of PTHrP and Ihh in regulating earlier steps in chondrocyte differentiation are unclear. We present novel mouse models with PPR abnormalities that help clarify these roles. In mice with chondrocyte-specific PPR ablation and mice with reduced PPR expression, chondrocyte differentiation was accelerated not only at the terminal step but also at an earlier step: periarticular to columnar differentiation. In these models, upregulation of Ihh action in the periarticular region was also observed. In the third model in which the PPR was disrupted in about 30% of columnar chondrocytes, Ihh action in the periarticular chondrocytes was upregulated because of ectopically differentiated hypertrophic chondrocytes that had lost PPR. Acceleration of periarticular to columnar differentiation was also noted in this mouse, while most of periarticular chondrocytes retained PPR signaling. These data suggest that Ihh positively controls differentiation of periarticular chondrocytes independently of PTHrP. Thus, chondrocyte differentiation is controlled at multiple steps by PTHrP and Ihh through the mutual regulation of their activities.
在发育中的小鼠生长板中，关节表面附近的软骨细胞（关节周围软骨细胞）增殖，分化为扁平柱状的增殖细胞（柱状软骨细胞），停止分裂并最终分化为肥大细胞。主要在肥大前细胞中表达的印度刺猬因子（Ihh）刺激甲状旁腺激素（PTH）相关肽（PTHrP）的表达，PTHrP通过PTH/PTHrP受体（PPR）对终末软骨细胞分化起负调节作用。然而，PTHrP和Ihh在调节软骨细胞分化早期步骤中的作用尚不清楚。我们提出了具有PPR异常的新型小鼠模型，有助于阐明这些作用。在软骨细胞特异性PPR缺失的小鼠和PPR表达降低的小鼠中，软骨细胞分化不仅在终末阶段加速，而且在更早阶段——从关节周围到柱状分化阶段也加速。在这些模型中，还观察到关节周围区域Ihh作用的上调。在第三个模型中，约30%的柱状软骨细胞中的PPR被破坏，由于异位分化且失去PPR的肥大软骨细胞，关节周围软骨细胞中的Ihh作用上调。在该小鼠中也注意到关节周围到柱状分化的加速，而大多数关节周围软骨细胞保留PPR信号。这些数据表明，Ihh独立于PTHrP对关节周围软骨细胞的分化起正向控制作用。因此，软骨细胞分化通过PTHrP和Ihh对其活性的相互调节在多个步骤中受到控制。
