Limits...
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.

Show MeSH

Related in: MedlinePlus

Knee joint histology in young MT-DNIIR mice. Images  of hematoxylin- and eosin-stained sections from wild-type (A, C,  and E) and MT-DNIIR (B, D, and F) knee joints at 4 wk of age.  Disorganized cartilage islands were often observed in the transgenic epiphysis (B, black arrowhead). Hypertrophic cells were located in the deep zones of the articular cartilage in transgenic (D)  but not wild-type (C) mice. Resting (RC), proliferating (PC), and  hypertrophic (HC) cells were easily detectable in the wild-type  growth plate (E). In transgenic mice, the histology of the growth  plate was altered. The hypertrophic zone was thicker, and two  distinct cell populations were observed, hypertrophic cells (HC)  and smaller, round prehypertrophic cells (PHC). Bars: (A and B)  400 μm; (C and D) 50 μm; (E and F) 77 μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2139797&req=5

Figure 6: Knee joint histology in young MT-DNIIR mice. Images of hematoxylin- and eosin-stained sections from wild-type (A, C, and E) and MT-DNIIR (B, D, and F) knee joints at 4 wk of age. Disorganized cartilage islands were often observed in the transgenic epiphysis (B, black arrowhead). Hypertrophic cells were located in the deep zones of the articular cartilage in transgenic (D) but not wild-type (C) mice. Resting (RC), proliferating (PC), and hypertrophic (HC) cells were easily detectable in the wild-type growth plate (E). In transgenic mice, the histology of the growth plate was altered. The hypertrophic zone was thicker, and two distinct cell populations were observed, hypertrophic cells (HC) and smaller, round prehypertrophic cells (PHC). Bars: (A and B) 400 μm; (C and D) 50 μm; (E and F) 77 μm.

Mentions: To determine the effects of DNIIR mRNA expression on joint histology, sections from wild-type and MT-DNIIR mouse knee joints at 4 wk (Fig. 6) and 6 mo (Fig. 7) of age were stained with hematoxylin and eosin. Some degeneration of the articular surface was observed at 4 wk. Patches of the articular surface were denuded of cartilage (Fig. 6 B), and hypertrophic cells were observed in the articular cartilage (Fig. 6 D). Furthermore, disorganized zones of cartilage were often seen in the epiphyseal head of long bones from mice at all ages (Fig. 6 B, black arrow). Alterations in the organization and histology of the growth plate were apparent at 4 (Fig. 6, E and F), and 8 wk (Fig. 8, C and D). In wild-type mice, cells in the growth plate exhibited normal columnar organization, and resting, proliferative, and hypertrophic zones were clearly demarcated (Fig. 6 E). In 4-wk-old transgenic mice, the hypertrophic zone was thicker and the cells in this zone were not organized in columnar arrays (Fig. 6 F). Resting and proliferating zones were visible, but the cells in the proliferating zone were sometimes grouped into clusters. A population of small, round cells not readily detectable in wild-type mice (Fig. 6 E) was located between the proliferating and hypertrophic zones (Fig. 6 F, PHC). In 8-wk-old transgenic mice, very few proliferating cells were seen. Most of the cells in the growth plate appeared hypertrophic and abnormally round (see Fig. 8 D).


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)

Knee joint histology in young MT-DNIIR mice. Images  of hematoxylin- and eosin-stained sections from wild-type (A, C,  and E) and MT-DNIIR (B, D, and F) knee joints at 4 wk of age.  Disorganized cartilage islands were often observed in the transgenic epiphysis (B, black arrowhead). Hypertrophic cells were located in the deep zones of the articular cartilage in transgenic (D)  but not wild-type (C) mice. Resting (RC), proliferating (PC), and  hypertrophic (HC) cells were easily detectable in the wild-type  growth plate (E). In transgenic mice, the histology of the growth  plate was altered. The hypertrophic zone was thicker, and two  distinct cell populations were observed, hypertrophic cells (HC)  and smaller, round prehypertrophic cells (PHC). Bars: (A and B)  400 μm; (C and D) 50 μm; (E and F) 77 μm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: Knee joint histology in young MT-DNIIR mice. Images of hematoxylin- and eosin-stained sections from wild-type (A, C, and E) and MT-DNIIR (B, D, and F) knee joints at 4 wk of age. Disorganized cartilage islands were often observed in the transgenic epiphysis (B, black arrowhead). Hypertrophic cells were located in the deep zones of the articular cartilage in transgenic (D) but not wild-type (C) mice. Resting (RC), proliferating (PC), and hypertrophic (HC) cells were easily detectable in the wild-type growth plate (E). In transgenic mice, the histology of the growth plate was altered. The hypertrophic zone was thicker, and two distinct cell populations were observed, hypertrophic cells (HC) and smaller, round prehypertrophic cells (PHC). Bars: (A and B) 400 μm; (C and D) 50 μm; (E and F) 77 μm.
Mentions: To determine the effects of DNIIR mRNA expression on joint histology, sections from wild-type and MT-DNIIR mouse knee joints at 4 wk (Fig. 6) and 6 mo (Fig. 7) of age were stained with hematoxylin and eosin. Some degeneration of the articular surface was observed at 4 wk. Patches of the articular surface were denuded of cartilage (Fig. 6 B), and hypertrophic cells were observed in the articular cartilage (Fig. 6 D). Furthermore, disorganized zones of cartilage were often seen in the epiphyseal head of long bones from mice at all ages (Fig. 6 B, black arrow). Alterations in the organization and histology of the growth plate were apparent at 4 (Fig. 6, E and F), and 8 wk (Fig. 8, C and D). In wild-type mice, cells in the growth plate exhibited normal columnar organization, and resting, proliferative, and hypertrophic zones were clearly demarcated (Fig. 6 E). In 4-wk-old transgenic mice, the hypertrophic zone was thicker and the cells in this zone were not organized in columnar arrays (Fig. 6 F). Resting and proliferating zones were visible, but the cells in the proliferating zone were sometimes grouped into clusters. A population of small, round cells not readily detectable in wild-type mice (Fig. 6 E) was located between the proliferating and hypertrophic zones (Fig. 6 F, PHC). In 8-wk-old transgenic mice, very few proliferating cells were seen. Most of the cells in the growth plate appeared hypertrophic and abnormally round (see Fig. 8 D).

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