Role of ADAMTS-3 in Procollagen Processing

描述（由申请方提供）：原胶原II和I的N-前肽的去除是正确的原纤维组装所必需的。前胶原I/II N-前肽酶（ADAMTS家族的一个成员（ADAMTS-2））中的突变引起复发性遗传性皮肤病，人类的Ehlers-Danlos综合征VIIC（皮肤麻痹型）和多种动物的皮肤麻痹。这种疾病的分子标志是存在含有完整N-前肽的胶原蛋白的异常原纤维。有趣的是，虽然原胶原I是骨骼、韧带、巩膜和主动脉的主要成分，但这些组织相对正常。在这些组织和皮肤中存在完全加工的胶原I，以及在皮肤松弛软骨中存在正常的前胶原II加工，表明存在其他N-前肽酶。ADAMTS-2、ADAMTS-3和ADAMTS-14包含ADAMTS家族的前胶原N-肽酶原酶（PCNP）组的总基因组补体。ADAMTS-14处理前胶原1，尽管效率低下。我们最近发现ADAMTS-3处理II型前胶原的N-前肽，是软骨中表达的主要PCNP。 本研究的假设是ADAMTS-3是主要的II型前胶原N-前肽酶，可能有助于在某些组织中加工I型前胶原。我们将通过产生和分析具有失活的Adamts-3等位基因的转基因小鼠来研究ADAMTS-3的精确生物学作用。 拟议研究的意义在于，它们提供了对前胶原加工和皮肤松弛的基础生物学的见解，并可能揭示ADAMTS-3的新生物学作用。从长远来看，这些信息可能对皮肤病的治疗有用。

DESCRIPTION (provided by applicant): Removal of the N-propeptide of procollagen II and I is required for proper fibril assembly. Mutations in procollagen I/II N-propeptidase, a member of the ADAMTS family (ADAMTS-2) cause a recessively inherited skin disorder, Ehlers-Danlos syndrome VIIC (dermatosparactic type) in humans and dermatosparaxis in a variety of animals. The molecular hallmark of this disorder is the presence of abnormal fibrils containing Collagen with an intact N-propeptide. Intriguingly, while procollagen I is a major component of bone, ligament, sclera and aorta, these tissues are relatively normal. The presence of fully processed Collagen I in these tissues and skin, as well as normal procollagen II processing in dermatosparactic cartilage suggests the presence of other N-propeptidases. ADAMTS-2, ADAMTS-3 and ADAMTS-14 comprise the total genomic complement of the procollagen N-propepticlase (PCNP) group of the ADAMTS family. ADAMTS-14 processes procollagen 1, albeit inefficiently. We recently discovered that ADAMTS-3 processes the N-propeptide of procollagen II and is the major PCNP expressed in cartilage. The hypothesis of this study is that ADAMTS-3 is the major procollagen II N-propeptidase and may contribute to procollagen I processing in some tissues. We will investigate the precise biological role(s) of ADAMTS-3 by generation and analysis of transgenic mice with inactivated Adamts3 alleles. The significance of the proposed studies is that they offer insights on the fundamental biology of procollagen processing and dermatosparaxis and may uncover novel biological roles for ADAMTS-3. In the long-term, this information may be useful for treatment of dermatosparaxis.