Sun Mei, Connizzo Brianne K, Adams Sheila M, Freedman Benjamin R, Wenstrup Richard J, Soslowsky Louis J, Birk David E
Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida.
McKay Orthopedic Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania.
Am J Pathol. 2015 May;185(5):1436-47. doi: 10.1016/j.ajpath.2015.01.031. Epub 2015 Mar 20.
Collagen V mutations underlie classic Ehlers-Danlos syndrome, and joint hypermobility is an important clinical manifestation. We define the function of collagen V in tendons and ligaments, as well as the role of alterations in collagen V expression in the pathobiology in classic Ehlers-Danlos syndrome. A conditional Col5a1(flox/flox) mouse model was bred with Scleraxis-Cre mice to create a targeted tendon and ligament Col5a1-null mouse model, Col5a1(Δten/Δten). Targeting was specific, resulting in collagen V-null tendons and ligaments. Col5a1(Δten/Δten) mice demonstrated decreased body size, grip weakness, abnormal gait, joint laxity, and early-onset osteoarthritis. These gross changes were associated with abnormal fiber organization, as well as altered collagen fibril structure with increased fibril diameters and decreased fibril number that was more severe in a major joint stabilizing ligament, the anterior cruciate ligament (ACL), than in the flexor digitorum longus tendon. The ACL also had a higher collagen V content than did the flexor digitorum longus tendon. The collagen V-null ACL and flexor digitorum longus tendon both had significant alterations in mechanical properties, with ACL exhibiting more severe changes. The data demonstrate critical differential regulatory roles for collagen V in tendon and ligament structure and function and suggest that collagen V regulatory dysfunction is associated with an abnormal joint phenotype, similar to the hypermobility phenotype in classic Ehlers-Danlos syndrome.
Ⅴ型胶原蛋白突变是典型埃勒斯-当洛综合征的病因，关节过度活动是该疾病的一项重要临床表现。我们确定了Ⅴ型胶原蛋白在肌腱和韧带中的功能，以及Ⅴ型胶原蛋白表达改变在典型埃勒斯-当洛综合征病理生物学中的作用。我们将条件性Col5a1（flox/flox）小鼠模型与Scleraxis-Cre小鼠杂交，以创建靶向性肌腱和韧带Col5a1基因敲除小鼠模型Col5a1（Δten/Δten）。靶向作用具有特异性，导致肌腱和韧带中缺乏Ⅴ型胶原蛋白。Col5a1（Δten/Δten）小鼠表现出体型减小、握力减弱、步态异常、关节松弛和早发性骨关节炎。这些大体变化与纤维组织异常有关，同时胶原原纤维结构也发生改变，原纤维直径增加，数量减少，在主要的关节稳定韧带——前交叉韧带（ACL）中比在趾长屈肌腱中更严重。ACL中的Ⅴ型胶原蛋白含量也高于趾长屈肌腱。缺乏Ⅴ型胶原蛋白的ACL和趾长屈肌腱的力学性能均有显著改变，ACL的变化更为严重。这些数据证明了Ⅴ型胶原蛋白在肌腱和韧带结构与功能中起关键的差异调节作用，并表明Ⅴ型胶原蛋白调节功能障碍与异常关节表型有关，类似于典型埃勒斯-当洛综合征中的关节过度活动表型。
