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Bone abnormalities in latent TGF-[beta] binding protein (Ltbp)-3- mice indicate a role for Ltbp-3 in modulating TGF-[beta] bioavailability.

Dabovic B, Chen Y, Colarossi C, Obata H, Zambuto L, Perle MA, Rifkin DB - J. Cell Biol. (2002)

Bottom Line: Between 6 and 9 mo of age, mutant animals also develop osteosclerosis and osteoarthritis.The pathological changes of the Ltbp-3- mice are consistent with perturbed TGF-beta signaling in the skull and long bones.Moreover, the results provide the first in vivo indication for a role of LTBP in modulating TGF-beta bioavailability.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA. dabovb01@med.nyu.edu

ABSTRACT
The TGF-betas are multifunctional proteins whose activities are believed to be controlled by interaction with the latent TGF-beta binding proteins (LTBPs). In spite of substantial effort, the precise in vivo significance of this interaction remains unknown. To examine the role of the Ltbp-3, we made an Ltbp-3- mutation in the mouse by gene targeting. Homozygous mutant animals develop cranio-facial malformations by day 10. At 2 mo, there is a pronounced rounding of the cranial vault, extension of the mandible beyond the maxilla, and kyphosis. Histological examination of the skulls from animals revealed ossification of the synchondroses within 2 wk of birth, in contrast to the wild-type synchondroses, which never ossify. Between 6 and 9 mo of age, mutant animals also develop osteosclerosis and osteoarthritis. The pathological changes of the Ltbp-3- mice are consistent with perturbed TGF-beta signaling in the skull and long bones. These observations give support to the notion that LTBP-3 is important for the control of TGF-beta action. Moreover, the results provide the first in vivo indication for a role of LTBP in modulating TGF-beta bioavailability.

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Changes in the structure of long bones in Ltbp 3 mice. (A–F) Mid-sagittal sections of tibiae (A and B) and caudal vertebrae (C–F) of 9-mo-old wild-type (A, C, and E) and mutant (B, D, and F) animals stained with Weingart hematoxylin/Safranin O/Fast green. (E and F) Higher (5×) magnification of the regions boxed in C and D. (G and H) Mid-sagittal sections of the articular region of proximal tibiae in 6-mo-old wild-type (E) and mutant mice (F). (I and J). Mid-sagittal section of epiphyses of 9-mo-old wild-type and Ltbp-3– mice. ac, articular cartilage; as, articular surface; gp, growth plate; arrowheads, hypertrophic chondrocytes.
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fig5: Changes in the structure of long bones in Ltbp 3 mice. (A–F) Mid-sagittal sections of tibiae (A and B) and caudal vertebrae (C–F) of 9-mo-old wild-type (A, C, and E) and mutant (B, D, and F) animals stained with Weingart hematoxylin/Safranin O/Fast green. (E and F) Higher (5×) magnification of the regions boxed in C and D. (G and H) Mid-sagittal sections of the articular region of proximal tibiae in 6-mo-old wild-type (E) and mutant mice (F). (I and J). Mid-sagittal section of epiphyses of 9-mo-old wild-type and Ltbp-3– mice. ac, articular cartilage; as, articular surface; gp, growth plate; arrowheads, hypertrophic chondrocytes.

Mentions: Because TGF-β has been shown to be important for long bone physiology, we examined the structure of the long bones of Ltbp-3– mice to determine if other TGF-β-mediated functions were affected. By day 8 after birth, animals showed growth retardation. The weight of adult Ltbp-3– animals was 30–80% of sex-matched littermates, and the endochondral bones were shorter by ∼10–25%. Histological analysis of the growth plates of tibiae, femora, and vertebrae from 1 d to 2-mo-old animals revealed no obvious differences between Ltbp-3– and wild-type littermates (unpublished data). Consistent with the report of Filvaroff et al. (1999), who expressed a type II TGF-β receptor with a truncated cytoplasmic domain (RIIDN) in osteoblasts and found age-dependent increases in trabecular bone mass, increased trabecular mass in long bones was observed at 3 mo of age in Ltbp-3– mice with a body weight <60% of sex-matched wild-type littermates (unpublished data). This osteosclerosis was more pronounced in 6- and 9-mo-old mutant animals (Fig. 5 , compare A and B). Staining for proteoglycans revealed unmineralized cores within the trabecular bones close to the growth plates, suggesting rapid extracellular matrix deposition and initiation of trabecular bone formation. The increased number of metaphysial trabeculae also suggested slow turnover. Similar changes occurred in the vertebrae (5, C–F). Interestingly, mutations in LAP cause Camurati–Engelmann syndrome, which is characterized by sclerosis and hyperosteosis (Janssens et al., 2000; Kinoshita et al., 2000), whereas transgenic animals overexpressing TGF-β2 in osteoblasts develop osteoporosis (Erlebacher and Derynck, 1996). Hence, we conclude that an Ltbp-3 defect mirrors long bone phenotypes caused by impaired TGF-β signaling.


Bone abnormalities in latent TGF-[beta] binding protein (Ltbp)-3- mice indicate a role for Ltbp-3 in modulating TGF-[beta] bioavailability.

Dabovic B, Chen Y, Colarossi C, Obata H, Zambuto L, Perle MA, Rifkin DB - J. Cell Biol. (2002)

Changes in the structure of long bones in Ltbp 3 mice. (A–F) Mid-sagittal sections of tibiae (A and B) and caudal vertebrae (C–F) of 9-mo-old wild-type (A, C, and E) and mutant (B, D, and F) animals stained with Weingart hematoxylin/Safranin O/Fast green. (E and F) Higher (5×) magnification of the regions boxed in C and D. (G and H) Mid-sagittal sections of the articular region of proximal tibiae in 6-mo-old wild-type (E) and mutant mice (F). (I and J). Mid-sagittal section of epiphyses of 9-mo-old wild-type and Ltbp-3– mice. ac, articular cartilage; as, articular surface; gp, growth plate; arrowheads, hypertrophic chondrocytes.
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Related In: Results  -  Collection

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fig5: Changes in the structure of long bones in Ltbp 3 mice. (A–F) Mid-sagittal sections of tibiae (A and B) and caudal vertebrae (C–F) of 9-mo-old wild-type (A, C, and E) and mutant (B, D, and F) animals stained with Weingart hematoxylin/Safranin O/Fast green. (E and F) Higher (5×) magnification of the regions boxed in C and D. (G and H) Mid-sagittal sections of the articular region of proximal tibiae in 6-mo-old wild-type (E) and mutant mice (F). (I and J). Mid-sagittal section of epiphyses of 9-mo-old wild-type and Ltbp-3– mice. ac, articular cartilage; as, articular surface; gp, growth plate; arrowheads, hypertrophic chondrocytes.
Mentions: Because TGF-β has been shown to be important for long bone physiology, we examined the structure of the long bones of Ltbp-3– mice to determine if other TGF-β-mediated functions were affected. By day 8 after birth, animals showed growth retardation. The weight of adult Ltbp-3– animals was 30–80% of sex-matched littermates, and the endochondral bones were shorter by ∼10–25%. Histological analysis of the growth plates of tibiae, femora, and vertebrae from 1 d to 2-mo-old animals revealed no obvious differences between Ltbp-3– and wild-type littermates (unpublished data). Consistent with the report of Filvaroff et al. (1999), who expressed a type II TGF-β receptor with a truncated cytoplasmic domain (RIIDN) in osteoblasts and found age-dependent increases in trabecular bone mass, increased trabecular mass in long bones was observed at 3 mo of age in Ltbp-3– mice with a body weight <60% of sex-matched wild-type littermates (unpublished data). This osteosclerosis was more pronounced in 6- and 9-mo-old mutant animals (Fig. 5 , compare A and B). Staining for proteoglycans revealed unmineralized cores within the trabecular bones close to the growth plates, suggesting rapid extracellular matrix deposition and initiation of trabecular bone formation. The increased number of metaphysial trabeculae also suggested slow turnover. Similar changes occurred in the vertebrae (5, C–F). Interestingly, mutations in LAP cause Camurati–Engelmann syndrome, which is characterized by sclerosis and hyperosteosis (Janssens et al., 2000; Kinoshita et al., 2000), whereas transgenic animals overexpressing TGF-β2 in osteoblasts develop osteoporosis (Erlebacher and Derynck, 1996). Hence, we conclude that an Ltbp-3 defect mirrors long bone phenotypes caused by impaired TGF-β signaling.

Bottom Line: Between 6 and 9 mo of age, mutant animals also develop osteosclerosis and osteoarthritis.The pathological changes of the Ltbp-3- mice are consistent with perturbed TGF-beta signaling in the skull and long bones.Moreover, the results provide the first in vivo indication for a role of LTBP in modulating TGF-beta bioavailability.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA. dabovb01@med.nyu.edu

ABSTRACT
The TGF-betas are multifunctional proteins whose activities are believed to be controlled by interaction with the latent TGF-beta binding proteins (LTBPs). In spite of substantial effort, the precise in vivo significance of this interaction remains unknown. To examine the role of the Ltbp-3, we made an Ltbp-3- mutation in the mouse by gene targeting. Homozygous mutant animals develop cranio-facial malformations by day 10. At 2 mo, there is a pronounced rounding of the cranial vault, extension of the mandible beyond the maxilla, and kyphosis. Histological examination of the skulls from animals revealed ossification of the synchondroses within 2 wk of birth, in contrast to the wild-type synchondroses, which never ossify. Between 6 and 9 mo of age, mutant animals also develop osteosclerosis and osteoarthritis. The pathological changes of the Ltbp-3- mice are consistent with perturbed TGF-beta signaling in the skull and long bones. These observations give support to the notion that LTBP-3 is important for the control of TGF-beta action. Moreover, the results provide the first in vivo indication for a role of LTBP in modulating TGF-beta bioavailability.

Show MeSH
Related in: MedlinePlus