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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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IHH and PTH receptor expression. Sections  of knee joints from 8 wk  wild-type (A and C) and MT-DNIIR transgenic (B and D)  mice were hybridized to 35S-labeled antisense IHH (A and  B) and PTH receptor (C and  D) riboprobes. Bars, 100 μm.
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Figure 9: IHH and PTH receptor expression. Sections of knee joints from 8 wk wild-type (A and C) and MT-DNIIR transgenic (B and D) mice were hybridized to 35S-labeled antisense IHH (A and B) and PTH receptor (C and D) riboprobes. Bars, 100 μm.

Mentions: IHH is a secreted protein expressed in chondrocytes committed to become hypertrophic and is thought to regulate cartilage differentiation (73, 74). When misexpressed in chick, IHH has been reported to induce PTHrP in perichondrial cells, which inhibits further differentiation of chondrocytes that express the PTH receptor; therefore, the negative-feedback effect of IHH on chondrocyte differentiation is indirect and is mediated by the perichondrium. Since the DNIIR is expressed in perichondrial cells (Fig. 4, B and C) and to gain insight into the role of TGF-β in chondrocyte differentiation, we examined IHH and PTH receptor expression in MT-DNIIR mice. Sections from 8-wk-old wild-type and transgenic knee joints were hybridized to 35S-labeled riboprobes. MT-DNIIR mice demonstrated higher levels of IHH expression in the growth plate relative to wild-type controls (Fig. 9, A and B). Expression was higher in each cell and IHH localized to a broader band of cells in the MT-DNIIR growth plate. PTH receptor was localized to prehypertrophic cells in wild-type and MT-DNIIR mice (Fig. 9, C and D). There was little difference in PTH receptor expression in the growth plate; however, there appeared to be a higher level of PTH receptor expression in osteoblasts in transgenic mice (Fig. 9 C). The altered expression of IHH suggests loss of responsiveness to TGF-βs, overrides the IHH feedback loop, and promotes commitment to terminal differentiation.


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)

IHH and PTH receptor expression. Sections  of knee joints from 8 wk  wild-type (A and C) and MT-DNIIR transgenic (B and D)  mice were hybridized to 35S-labeled antisense IHH (A and  B) and PTH receptor (C and  D) riboprobes. Bars, 100 μm.
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Related In: Results  -  Collection

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

Figure 9: IHH and PTH receptor expression. Sections of knee joints from 8 wk wild-type (A and C) and MT-DNIIR transgenic (B and D) mice were hybridized to 35S-labeled antisense IHH (A and B) and PTH receptor (C and D) riboprobes. Bars, 100 μm.
Mentions: IHH is a secreted protein expressed in chondrocytes committed to become hypertrophic and is thought to regulate cartilage differentiation (73, 74). When misexpressed in chick, IHH has been reported to induce PTHrP in perichondrial cells, which inhibits further differentiation of chondrocytes that express the PTH receptor; therefore, the negative-feedback effect of IHH on chondrocyte differentiation is indirect and is mediated by the perichondrium. Since the DNIIR is expressed in perichondrial cells (Fig. 4, B and C) and to gain insight into the role of TGF-β in chondrocyte differentiation, we examined IHH and PTH receptor expression in MT-DNIIR mice. Sections from 8-wk-old wild-type and transgenic knee joints were hybridized to 35S-labeled riboprobes. MT-DNIIR mice demonstrated higher levels of IHH expression in the growth plate relative to wild-type controls (Fig. 9, A and B). Expression was higher in each cell and IHH localized to a broader band of cells in the MT-DNIIR growth plate. PTH receptor was localized to prehypertrophic cells in wild-type and MT-DNIIR mice (Fig. 9, C and D). There was little difference in PTH receptor expression in the growth plate; however, there appeared to be a higher level of PTH receptor expression in osteoblasts in transgenic mice (Fig. 9 C). The altered expression of IHH suggests loss of responsiveness to TGF-βs, overrides the IHH feedback loop, and promotes commitment to terminal differentiation.

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