The role of the cartilage protein Ucma in degenerative and inflammatory arthritis

Ucma是最近发现的一种分泌软骨蛋白。它实际上只在软骨中表达，而在斑马鱼中被morpholino RNA敲低Ucma会导致骨骼发育严重紊乱。相反，缺乏ucma的小鼠发育正常。因此，迄今为止，Ucma在哺乳动物中的生物学作用在很大程度上是未知的，尽管我们之前已经证明Ucma在体外抑制小鼠和人类祖细胞的成骨分化。使用Ucma缺陷小鼠，我们在这里发现Ucma对实验性骨关节炎期间软骨完整性具有保护作用。此外，我们证明，在实验性骨关节炎期间，ucma缺陷小鼠不表现出骨硬化表型，其特征是在野生型小鼠中观察到的成骨细胞和破骨细胞数量增加。这表明在骨关节炎期间Ucma在软骨和骨之间的交流中有潜在的作用。在本项目中，我们将研究Ucma对实验性骨关节炎软骨完整性的保护机制。此外，我们将研究Ucma如何影响实验性骨关节炎的骨重塑，从而促进软骨-骨通讯。我们还将评估Ucma对实验性炎性关节炎中软骨损伤和骨转换的潜在影响。为了评估Ucma在治疗退行性和/或炎症性关节疾病中的潜在治疗潜力，我们将建立Ucma的功能获得小鼠模型，并研究存在或不存在过量Ucma的实验性骨关节炎和炎性关节炎的进展。最后，我们将研究Ucma在小鼠关节疾病中的作用是否可以转化为人类系统。

Ucma is a recently identified secreted cartilage protein. It is virtually exclusively expressed in cartilage, and knockdown of Ucma in zebrafish by morpholino RNA results in a severely disturbed skeletal development. In contrast, however, Ucma-deficient mice develop normally. Therefore, the biological role of Ucma in mammals is largely unknown to date, although we had previously shown that Ucma inhibits the osteogenic differentiation of murine and human progenitor cells in vitro. Using Ucma-deficient mice, we show here that Ucma has a protective effect on cartilage integrity during experimental osteoarthritis. Moreover, we demonstrate that during experimental osteoarthritis Ucma-deficient mice do not exhibit the sclerotic bone phenotype, characterised by an increase in osteoblast and osteoclast numbers, as observed in wild-type mice. This indicates a potential role of Ucma in the communication between cartilage and bone during osteoarthritis.During the proposed project we will investigate the protective mechanisms of Ucma on cartilage integrity during experimental osteoarthritis. Moreover, we will study, by which means Ucma affects bone remodelling in experimental osteoarthritis and thereby contributes to cartilage-bone communication. We will also assess a potential effect of Ucma on cartilage damage and bone turnover in experimental inflammatory arthritis. In order to evaluate a conceivable therapeutic potential of Ucma in the treatment of degenerative and/or inflammatory joint diseases, we will establish a gain-of-function mouse model for Ucma, and investigate the progression of experimental osteoarthritis and inflammatory arthritis in the presence or absence of excess levels of Ucma. Finally, we will investigate, whether the role of Ucma in murine joint diseases can be translated to the human system.