Cartilage Biology and Regenerative Medicine Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Department of OB/GYN, Division of Reproductive Sciences, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
FASEB J. 2020 Mar;34(3):4445-4461. doi: 10.1096/fj.201902287R. Epub 2020 Feb 6.
Temporomandibular joint osteoarthritis (TMJ OA) leads to permanent cartilage destruction, jaw dysfunction, and compromises the quality of life. However, the pathological mechanisms governing TMJ OA are poorly understood. Unlike appendicular articular cartilage, the TMJ has two distinct functions as the synovial joint of the craniofacial complex and also as the site for endochondral jaw bone growth. The established dogma of endochondral bone ossification is that hypertrophic chondrocytes undergo apoptosis, while invading vasculature with osteoprogenitors replace cartilage with bone. However, contemporary murine genetic studies support the direct differentiation of chondrocytes into osteoblasts and osteocytes in the TMJ. Here we sought to characterize putative vasculature and cartilage to bone transdifferentiation using healthy and diseased TMJ tissues from miniature pigs and humans. During endochondral ossification, the presence of fully formed vasculature expressing CD31 endothelial cells and α-SMA vascular smooth muscle cells were detected within all cellular zones in growing miniature pigs. Arterial, endothelial, venous, angiogenic, and mural cell markers were significantly upregulated in miniature pig TMJ tissues relative to donor matched knee meniscus fibrocartilage tissue. Upon surgically creating TMJ OA in miniature pigs, we discovered increased vasculature and putative chondrocyte to osteoblast transformation dually marked by COL2 and BSP or RUNX2 within the vascular bundles. Pathological human TMJ tissues also exhibited increased vasculature, while isolated diseased human TMJ cells exhibited marked increased in vasculature markers relative to control 293T cells. Our study provides evidence to suggest that the TMJ in higher order species are in fact vascularized. There have been no reports of cartilage to bone transdifferentiation or vasculature in human-relevant TMJ OA large animal models or in human TMJ tissues and cells. Therefore, these findings may potentially alter the clinical management of TMJ OA by defining new drugs that target angiogenesis or block the cartilage to bone transformation.
颞下颌关节骨关节炎（TMJ OA）导致永久性软骨破坏、下颌功能障碍，并降低生活质量。然而，导致 TMJ OA 的病理机制尚不清楚。与附肢关节软骨不同，TMJ 具有两个截然不同的功能，既是颅面复合体的滑膜关节，也是软骨内颌骨生长的部位。经典的软骨内成骨理论认为，肥大的软骨细胞凋亡，而侵入的血管和骨祖细胞取代软骨形成骨。然而，当代的小鼠遗传研究支持 TMJ 中的软骨细胞直接分化为成骨细胞和骨细胞。在这里，我们试图使用小型猪和人类的健康和患病 TMJ 组织来描述潜在的血管和软骨向骨的转化。在软骨内骨化过程中，在生长中的小型猪的所有细胞区均检测到完全形成的表达 CD31 内皮细胞和α-SMA 血管平滑肌细胞的血管。与供体匹配的膝关节半月板纤维软骨组织相比，小型猪 TMJ 组织中动脉、内皮、静脉、血管生成和壁细胞标志物显著上调。在小型猪 TMJ 中手术诱导 OA 后，我们发现血管数量增加，血管束内同时存在 COL2 和 BSP 或 RUNX2 双标记的软骨细胞向成骨细胞的转化。病理性人 TMJ 组织也表现出血管增加，而分离的患病人 TMJ 细胞与对照 293T 细胞相比，血管标志物表达显著增加。我们的研究提供了证据表明，高等动物的 TMJ 实际上是血管化的。在与人相关的 TMJ OA 大型动物模型或人 TMJ 组织和细胞中，尚未有关于软骨向骨转化或血管形成的报道。因此，这些发现可能通过定义靶向血管生成或阻断软骨向骨转化的新药，从而改变 TMJ OA 的临床管理。
