Friedrich Alexander University of Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Friedrich Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Arthritis Rheumatol. 2017 Jun;69(6):1233-1245. doi: 10.1002/art.40042. Epub 2017 Apr 24.
Cartilage damage and subchondral bone changes are closely connected in osteoarthritis. Nevertheless, how these processes are interlinked is, to date, incompletely understood. This study was undertaken to investigate the mechanistic role of a cartilage-derived protein, upper zone of growth plate and cartilage matrix-associated protein (UCMA), in osteoarthritis-related cartilage and bone changes.
UCMA expression was assessed in healthy and osteoarthritic human and mouse cartilage. For analysis of cartilage and bone changes, osteoarthritis was induced by destabilization of the medial meniscus (DMM) in wild-type (WT) and Ucma-deficient mice. UCMA-collagen interactions, the effect of UCMA on aggrecanase activity, and the impact of recombinant UCMA on osteoclast differentiation were studied in vitro.
UCMA was found to be overexpressed in human and mouse osteoarthritic cartilage. DMM-triggered cartilage changes, including increased structural damage, proteoglycan loss, and chondrocyte cell death, were aggravated in Ucma-deficient mice compared to WT littermates, thereby demonstrating the potential chondroprotective effects of UCMA. Moreover, UCMA inhibited ADAMTS-dependent aggrecanase activity and directly interacted with cartilage-specific collagen types. In contrast, osteoarthritis-related bone changes were significantly reduced in Ucma-deficient mice, showing less pronounced osteophyte formation and subchondral bone sclerosis. Mechanistically, UCMA directly promoted osteoclast differentiation in vitro.
UCMA appears to link cartilage with bone changes in osteoarthritis by supporting cartilage integrity as an endogenous inhibitor of aggrecanases while also promoting osteoclastogenesis and subchondral bone turnover. Thus, UCMA represents an important link between cartilage and bone in osteoarthritis.
在骨关节炎中，软骨损伤和软骨下骨改变密切相关。然而，这些过程是如何相互关联的，目前还不完全清楚。本研究旨在探讨软骨源性蛋白、生长板上区和软骨基质相关蛋白（UCMA）在骨关节炎相关软骨和骨变化中的机制作用。
评估了健康和骨关节炎患者的人及鼠软骨中的 UCMA 表达。为了分析软骨和骨变化，通过内侧半月板不稳定（DMM）在野生型（WT）和 Ucma 缺陷型小鼠中诱导骨关节炎。在体外研究了 UCMA-胶原相互作用、UCMA 对聚集蛋白酶活性的影响以及重组 UCMA 对破骨细胞分化的影响。
发现 UCMA 在人及鼠骨关节炎软骨中过度表达。与 WT 同窝仔鼠相比，DMM 触发的软骨变化，包括结构损伤增加、蛋白聚糖丢失和软骨细胞死亡，在 Ucma 缺陷型小鼠中加重，从而表明 UCMA 具有潜在的软骨保护作用。此外，UCMA 抑制 ADAMTS 依赖性聚集蛋白酶活性，并直接与软骨特异性胶原类型相互作用。相比之下，Ucma 缺陷型小鼠的骨关节炎相关骨变化明显减少，骨赘形成和软骨下骨硬化程度较低。机制上，UCMA 直接促进体外破骨细胞分化。
UCMA 似乎通过支持软骨完整性作为聚集蛋白酶的内源性抑制剂，同时促进破骨细胞生成和软骨下骨转换，将软骨与骨关节炎的骨变化联系起来。因此，UCMA 是骨关节炎中软骨和骨之间的重要联系。
