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Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis.

Serra R, Johnson M, Filvaroff EH, LaBorde J, Sheehan DM, Derynck R, Moses HL - J. Cell Biol. (1997)

Bottom Line: Lower levels of DNIIR mRNA were detected in growth plate cartilage.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-beta may be critical for multifaceted maintenance of synovial joints.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and the Vanderbilt Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA.

ABSTRACT
Members of the TGF-beta superfamily are important regulators of skeletal development. TGF-betas 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-betas 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-beta 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-beta may be critical for multifaceted maintenance of synovial joints. Loss of responsiveness to TGF-beta promotes chondrocyte terminal differentiation and results in development of degenerative joint disease resembling osteoarthritis in humans.

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Skeletal defects in MT-DNIIR transgenic mice. Photographs of alizarin red whole mount skeletal preparations from  adult wild-type (A, C, E, G, and I) MTR-DNIIR-4 (B, D, H, and  J), and MT-DNIIR-27 (F) mice. Arrows point to xiphoid process  (A and B), knee (C–F), shoulder (G and H) joints, and cervical  vertebrae (I and J).
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Figure 2: Skeletal defects in MT-DNIIR transgenic mice. Photographs of alizarin red whole mount skeletal preparations from adult wild-type (A, C, E, G, and I) MTR-DNIIR-4 (B, D, H, and J), and MT-DNIIR-27 (F) mice. Arrows point to xiphoid process (A and B), knee (C–F), shoulder (G and H) joints, and cervical vertebrae (I and J).

Mentions: Signs of skeletal abnormalities were observed in mice from two of the MT-DNIIR transgenic lines, MT-DNIIR-4 and MT-DNIIR-27, maintained on normal food and tap water. Defects were observed in heterozygous mice. Skeletal defects were apparent by 3 mo of age and became progressively worse as the mice aged. MT-DNIIR-4 mice demonstrated kyphoscoliosis and stiffness in the hindlimb joints. In some cases, hindlimbs were torqued laterally at varying angles. The xiphoid process of the sternum protruded out from the chest and was visible under the skin. MT-DNIIR-27 mice demonstrated stiffness in the knees. No differences in bone density were detected on X-ray films (data not shown). To further characterize the nature of the skeletal defects, alizarin red whole mount skeletal preparations of adult mice (4 to 8 mo of age) were performed (Table I; Fig. 2). A summary of skeletal defects observed in whole mount skeletal preparation of adult wild-type and heterozygous transgenic mice is shown in Table I. Representative preparations are shown from adult wild-type, MT-DNIIR-4, and MT-DNIIR-27 mice (Fig. 2). The xiphoid process of adult MT-DNIIR-4 transgenic animals was bifurcated. Knee and shoulder joints of MT-DNIIR-4 and -27 mice were disorganized and contained excess calcified tissue. MT-DNIIR-4 vertebrae were often misshapen and appeared fused. Sternal defects and tumoral calcinosis were only found in the MT-DNIIR-4 line; therefore, these observations must be considered tentative. However, the presence of joint defects in two transgenic lines suggests the reasonable hypothesis that all the chondrocyte abnormalities in MT-DNIIR-4 mice are not simply insertional effects. Skeletal defects were not detected in wild-type mice.


Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis.

Serra R, Johnson M, Filvaroff EH, LaBorde J, Sheehan DM, Derynck R, Moses HL - J. Cell Biol. (1997)

Skeletal defects in MT-DNIIR transgenic mice. Photographs of alizarin red whole mount skeletal preparations from  adult wild-type (A, C, E, G, and I) MTR-DNIIR-4 (B, D, H, and  J), and MT-DNIIR-27 (F) mice. Arrows point to xiphoid process  (A and B), knee (C–F), shoulder (G and H) joints, and cervical  vertebrae (I and J).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2139797&req=5

Figure 2: Skeletal defects in MT-DNIIR transgenic mice. Photographs of alizarin red whole mount skeletal preparations from adult wild-type (A, C, E, G, and I) MTR-DNIIR-4 (B, D, H, and J), and MT-DNIIR-27 (F) mice. Arrows point to xiphoid process (A and B), knee (C–F), shoulder (G and H) joints, and cervical vertebrae (I and J).
Mentions: Signs of skeletal abnormalities were observed in mice from two of the MT-DNIIR transgenic lines, MT-DNIIR-4 and MT-DNIIR-27, maintained on normal food and tap water. Defects were observed in heterozygous mice. Skeletal defects were apparent by 3 mo of age and became progressively worse as the mice aged. MT-DNIIR-4 mice demonstrated kyphoscoliosis and stiffness in the hindlimb joints. In some cases, hindlimbs were torqued laterally at varying angles. The xiphoid process of the sternum protruded out from the chest and was visible under the skin. MT-DNIIR-27 mice demonstrated stiffness in the knees. No differences in bone density were detected on X-ray films (data not shown). To further characterize the nature of the skeletal defects, alizarin red whole mount skeletal preparations of adult mice (4 to 8 mo of age) were performed (Table I; Fig. 2). A summary of skeletal defects observed in whole mount skeletal preparation of adult wild-type and heterozygous transgenic mice is shown in Table I. Representative preparations are shown from adult wild-type, MT-DNIIR-4, and MT-DNIIR-27 mice (Fig. 2). The xiphoid process of adult MT-DNIIR-4 transgenic animals was bifurcated. Knee and shoulder joints of MT-DNIIR-4 and -27 mice were disorganized and contained excess calcified tissue. MT-DNIIR-4 vertebrae were often misshapen and appeared fused. Sternal defects and tumoral calcinosis were only found in the MT-DNIIR-4 line; therefore, these observations must be considered tentative. However, the presence of joint defects in two transgenic lines suggests the reasonable hypothesis that all the chondrocyte abnormalities in MT-DNIIR-4 mice are not simply insertional effects. Skeletal defects were not detected in wild-type mice.

Bottom Line: Lower levels of DNIIR mRNA were detected in growth plate cartilage.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-beta may be critical for multifaceted maintenance of synovial joints.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and the Vanderbilt Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA.

ABSTRACT
Members of the TGF-beta superfamily are important regulators of skeletal development. TGF-betas 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-betas 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-beta 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-beta may be critical for multifaceted maintenance of synovial joints. Loss of responsiveness to TGF-beta promotes chondrocyte terminal differentiation and results in development of degenerative joint disease resembling osteoarthritis in humans.

Show MeSH
Related in: MedlinePlus