Krönke Gerhard, Uderhardt Stefan, Kim Kyung-Ah, Stock Michael, Scholtysek Carina, Zaiss Mario M, Surmann-Schmitt Cordula, Luther Julia, Katzenbeisser Julia, David Jean-Pierre, Abdollahi-Roodsaz Shahla, Tran Karolyn, Bright Jessica M, Binnerts Minke E, Akhmetshina Alfiya, Böhm Christina, Distler Jörg H, Joosten Leo A B, Schett Georg, Abo Arie
University of Erlangen-Nuremberg, Erlangen, Germany.
Arthritis Rheum. 2010 Aug;62(8):2303-12. doi: 10.1002/art.27496.
During the course of different musculoskeletal diseases, joints are progressively damaged by inflammatory, infectious, or mechanical stressors, leading to joint destruction and disability. While effective strategies to inhibit joint inflammation, such as targeted cytokine-blocking therapy, have been developed during the last decade, the molecular mechanisms of joint damage are still poorly understood. This study was undertaken to investigate the role of the Wnt pathway modulator R-Spondin 1 (RSpo1) in protecting bone and cartilage in a mouse model of arthritis.
Tumor necrosis factor alpha (TNFalpha)-transgenic mice were treated with vehicle or Rspo1. Mice were evaluated for signs of arthritis, and histologic analysis of the hind paws was performed. Moreover, we determined the effect of Rspo1 on Wnt signaling activity and osteoprotegerin (OPG) expression in murine primary osteoblasts.
The secreted Wnt pathway modulator RSpo1 was highly effective in preserving the structural integrity of joints in a TNFalpha-transgenic mouse model of arthritis by protecting bone and cartilage from inflammation-related damage. RSpo1 antagonized the Wnt inhibitor Dkk-1 and modulated Wnt signaling in mouse mesenchymal cells. In osteoblasts, RSpo1 induced differentiation and expression of OPG, thereby inhibiting osteoclastogenesis in vitro. In vivo, RSpo1 promoted osteoblast differentiation and bone formation while blocking osteoclast development, thereby contributing to the integrity of joints during inflammatory arthritis.
Our results demonstrate the therapeutic potential of RSpo1 as an anabolic agent for the preservation of joint architecture.
在不同肌肉骨骼疾病的病程中，关节会因炎症、感染或机械应激源而逐渐受损，导致关节破坏和残疾。尽管在过去十年中已开发出抑制关节炎症的有效策略，如靶向细胞因子阻断疗法，但关节损伤的分子机制仍知之甚少。本研究旨在探讨Wnt通路调节剂R-Spondin 1（RSpo1）在关节炎小鼠模型中保护骨骼和软骨的作用。
用载体或Rspo1处理肿瘤坏死因子α（TNFα）转基因小鼠。评估小鼠的关节炎体征，并对后爪进行组织学分析。此外，我们测定了Rspo1对小鼠原代成骨细胞中Wnt信号活性和骨保护素（OPG）表达的影响。
分泌型Wnt通路调节剂RSpo1在TNFα转基因关节炎小鼠模型中通过保护骨骼和软骨免受炎症相关损伤，对维持关节结构完整性非常有效。RSpo1拮抗Wnt抑制剂Dkk-1并调节小鼠间充质细胞中的Wnt信号。在成骨细胞中，RSpo1诱导OPG的分化和表达，从而在体外抑制破骨细胞生成。在体内，RSpo1促进成骨细胞分化和骨形成，同时阻断破骨细胞发育，从而在炎症性关节炎期间有助于维持关节的完整性。
我们的结果证明了RSpo1作为一种合成代谢剂在维持关节结构方面的治疗潜力。
