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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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Ltbp-3 targeting strategy. LTBP-3 protein structure. The region deleted in the targeted locus is underlined.
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fig1: Ltbp-3 targeting strategy. LTBP-3 protein structure. The region deleted in the targeted locus is underlined.

Mentions: The latent TGF-β binding proteins (LTBPs)*-1–4 are matrix molecules composed of multiple (14–20) EGF-like domains and four domains containing eight cysteines (8-cys) that are specific for the LTBPs and the fibrillins (for review see Handford et al., 2000; Koli et al., 2001). The modular structure of Ltbp-3 is shown in Fig. 1 A (Yin et al., 1995). LTBP-1, 3, and 4 covalently bind latent TGF-β (Koli et al., 2001). The TGF-βs are 25-kd homodimeric cytokines derived by intracellular proteolytic processing of larger proproteins (Massague, 1998). However, once cleaved from the cytokine, the TGF-β propeptide, called the latency-associated peptide (LAP), remains noncovalently associated with the mature TGF-β after secretion (Koli et al., 2001). This complex of TGF-β and LAP, the small latent complex, is inactive, and the dissociation of TGF-β from LAP is a crucial regulatory step in TGF-β action. The small latent complex can form a large latent complex by the bonding of cysteines in the LAP with a pair of cysteines in the third 8-cys domain of LTBP (Gleizes et al., 1996; Saharinen et al., 1996). All three TGF-β isoforms bind to LTBPs-1, 3, or 4; however, neither LTBP-2 nor the fibrillins bind TGF-β (Saharinen and Keski-Oja, 2000).


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)

Ltbp-3 targeting strategy. LTBP-3 protein structure. The region deleted in the targeted locus is underlined.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199217&req=5

fig1: Ltbp-3 targeting strategy. LTBP-3 protein structure. The region deleted in the targeted locus is underlined.
Mentions: The latent TGF-β binding proteins (LTBPs)*-1–4 are matrix molecules composed of multiple (14–20) EGF-like domains and four domains containing eight cysteines (8-cys) that are specific for the LTBPs and the fibrillins (for review see Handford et al., 2000; Koli et al., 2001). The modular structure of Ltbp-3 is shown in Fig. 1 A (Yin et al., 1995). LTBP-1, 3, and 4 covalently bind latent TGF-β (Koli et al., 2001). The TGF-βs are 25-kd homodimeric cytokines derived by intracellular proteolytic processing of larger proproteins (Massague, 1998). However, once cleaved from the cytokine, the TGF-β propeptide, called the latency-associated peptide (LAP), remains noncovalently associated with the mature TGF-β after secretion (Koli et al., 2001). This complex of TGF-β and LAP, the small latent complex, is inactive, and the dissociation of TGF-β from LAP is a crucial regulatory step in TGF-β action. The small latent complex can form a large latent complex by the bonding of cysteines in the LAP with a pair of cysteines in the third 8-cys domain of LTBP (Gleizes et al., 1996; Saharinen et al., 1996). All three TGF-β isoforms bind to LTBPs-1, 3, or 4; however, neither LTBP-2 nor the fibrillins bind TGF-β (Saharinen and Keski-Oja, 2000).

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