ROLE OF DIFFERENTIATION FACTORS IN CARTILAGE AND BONE FORMATION AND REGENERATION

我们已经在软骨中发现了半胱氨酸对酪氨酸的替代- 衍生形态发生蛋白-1(CDMP-1)是一种致病突变 临床严重障碍，Grebe型软骨发育不良(OMIM编号 200700)。这种常染色体隐性遗传病的纯合子个体 表现出严重的肢体缩短，并伴有手指和关节异常。这个 受影响的肢体比上肢和四肢的程度 短缩是从近端到远端方向进行的。我们已经研究过 突变的潜在机制并已发现有缺陷的 CDMP-1不被加工或分泌，并阻止其他， 相关的骨形态发生蛋白(BMP)通过形成 杂二聚体。这种类型的突变称为显性阴性，是 这是转化生长因子-β超家族中第一例这种突变。它的 提议的行动机制提供了第一个令人信服的证据 体内相关BMP间形成异二聚体。 我们已经与一家工业企业建立了合作协议(CRADA) 合作伙伴为我们提供重组CDMP。这使得我们能够 阐述CDMP的生物学功能并比较它们的生物学功能 与其他BMP的配置文件。我们的数据表明CDMP在功能上是 与BMPs相关，能够诱导软骨和骨骼 在活体大鼠的皮下部位形成。有趣的是，在那里 是优先刺激软骨生成，而不是成骨 与其他骨形态发生蛋白相比。我们认为，潜在的机制 这种偏爱的软骨生成活动可能与他们的 特定BMP受体复合体的结合亲和力。

We have identified a cysteine to tyrosine substitution in Cartilage- Derived Morphogenetic Protein-1 (CDMP-1) as the causative mutation of a clinically severe disorder, Grebe type chondrodyplasia (OMIM number 200700). Individuals homozygous for this autosomal recessive disorder exhibit severe limb shortening with digital and joint abnormalities. The lower limbs are affected more than the upper limbs and the degree of limb shortening progresses in a proximal to distal direction. We have studied the underlying mechanism of the mutation and have found that the defective CDMP-1 is not processed or secreted, and prevents the secretion of other, related, Bone morphogenetic Proteins (BMPs) through the formation of heterodimers. This type of mutation, called a dominant negative, is the first example of such a mutation in the TGF-beta superfamily. Its proposed mechanism of action provides the first compelling evidence for heterodimer formation between related BMPs in vivo. We have established a Collaborative Agreement (CRADA) with an industrial partner to provide us with recombinant CDMPs. This has allowed us to address the biological functions of CDMPs and compare their biological profile with other BMPs. Our data indicate that the CDMPs are functionally related to the BMPs and are capable of inducing cartilage and bone formation in an subcutaneous site in rats in vivo. Interestingly, there is a preferential stimulation of chondrogenesis as opposed to osteogenesis when compared with other BMPs. We propose that the underlying mechanism for this preferential chondrogenic activity is probably linked to their binding affinity for specific BMP receptor complexes.