Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis.
Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis.
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DOI：
10.1083/jcb.139.2.541
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发表时间：
1997-10-20
期刊：
影响因子：
--
通讯作者：
Moses HL
中科院分区：
文献类型：
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作者：
Serra R;Johnson M;Filvaroff EH;LaBorde J;Sheehan DM;Derynck R;Moses HL
TGF-β超家族成员是骨骼发育的重要调节因子。TGF-βs信号通过I型和II型受体丝氨酸/苏氨酸激酶传递。当过表达时，胞质截断的II型受体可以与内源性受体竞争形成复合物，从而作为显性负突变体（DNIIR）。为了确定TGF-βs在骨骼发育和维持中的作用，我们在骨组织中产生了表达DNIIR的转基因小鼠（MT-DNIIR-4和-27）。DNIIR mRNA的表达局限于骨膜/软骨膜、滑膜和关节软骨。生长板软骨中DNIIR mRNA表达水平较低。转基因小鼠经常出现剑突和胸骨分叉。他们还会出现进行性骨骼退化，导致4至8个月时出现脊柱后凸、关节僵硬和扭曲。受影响关节的组织学与人类骨关节炎非常相似。根据X型胶原蛋白的表达判断，关节表面被骨或增生性软骨所取代，X型胶原蛋白是关节软骨通常不存在的增生性软骨的标志。滑膜增生，关节间隙软骨化生。然后，我们验证了TGF-β是体内软骨正常分化所必需的假设。在4和8周龄时，转基因小鼠生长板软骨中X型胶原蛋白的水平相对于野生型对照组有所增加。转基因小鼠生长板和关节软骨基质蛋白聚糖染色较少。在骨组织中表达DNIIR的小鼠也表现出增加的印度刺猬（IHH）表达。IHH是一种分泌蛋白，在软骨细胞中表达，使软骨细胞变得肥大。它被认为参与了一个反馈回路，通过骨膜/软骨膜信号抑制软骨分化。数据表明TGF-β可能对滑膜关节的多方面维持至关重要。对TGF-β反应性的丧失促进软骨细胞终末分化并导致类似人类骨关节炎的退行性关节疾病的发展。
Members of the TGF-β superfamily are important regulators of skeletal development. TGF-βs signal through heteromeric type I and type II receptor serine/threonine kinases. When over-expressed, a cytoplasmically truncated type II receptor can compete with the endogenous receptors for complex formation, thereby acting as a dominant-negative mutant (DNIIR). To determine the role of TGF-βs in the development and maintenance of the skeleton, we have generated transgenic mice (MT-DNIIR-4 and -27) that express the DNIIR in skeletal tissue. DNIIR mRNA expression was localized to the periosteum/perichondrium, syno-vium, and articular cartilage. Lower levels of DNIIR mRNA were detected in growth plate cartilage. Transgenic mice frequently showed bifurcation of the xiphoid process and sternum. They also developed progressive skeletal degeneration, resulting by 4 to 8 mo of age in kyphoscoliosis and stiff and torqued joints. The histology of affected joints strongly resembled human osteo-arthritis. The articular surface was replaced by bone or hypertrophic cartilage as judged by the expression of type X collagen, a marker of hypertrophic cartilage normally absent from articular cartilage. The synovium was hyperplastic, and cartilaginous metaplasia was observed in the joint space. We then tested the hypothesis that TGF-β is required for normal differentiation of cartilage in vivo. By 4 and 8 wk of age, the level of type X collagen was increased in growth plate cartilage of transgenic mice relative to wild-type controls. Less proteoglycan staining was detected in the growth plate and articular cartilage matrix of transgenic mice. Mice that express DNIIR in skeletal tissue also demonstrated increased Indian hedgehog (IHH) expression. IHH is a secreted protein that is expressed in chondrocytes that are committed to becoming hypertrophic. It is thought to be involved in a feedback loop that signals through the periosteum/ perichondrium to inhibit cartilage differentiation. The data suggest that TGF-β may be critical for multifaceted maintenance of synovial joints. Loss of responsiveness to TGF-β promotes chondrocyte terminal differentiation and results in development of degenerative joint disease resembling osteoarthritis in humans.