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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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Histology of wild-type and Ltbp-3– skulls. (A and B) Fusion of bones of the skull base in 3-wk-old Ltbp-3 mice. Whole mount skulls of wild-type (A) and mutant (B) animals were stained with alcian blue for cartilage and Alizarin red S for calcified bone, and skull bases were dissected. Arrows point to synchondroses between occipital (oc), sphenoid (sp) and presphenoid (ps) bones. (C and D). Histology of the skull base of 3-wk-old wild-type (C) and Ltbp-3– (D) animals. Cartilage is stained red and bone blue. The basooccipital–basosphenoid synchondrosis is on the left.
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fig3: Histology of wild-type and Ltbp-3– skulls. (A and B) Fusion of bones of the skull base in 3-wk-old Ltbp-3 mice. Whole mount skulls of wild-type (A) and mutant (B) animals were stained with alcian blue for cartilage and Alizarin red S for calcified bone, and skull bases were dissected. Arrows point to synchondroses between occipital (oc), sphenoid (sp) and presphenoid (ps) bones. (C and D). Histology of the skull base of 3-wk-old wild-type (C) and Ltbp-3– (D) animals. Cartilage is stained red and bone blue. The basooccipital–basosphenoid synchondrosis is on the left.

Mentions: The appropriate anatomical development of the skull requires the coordinated growth of the membranous and endochondral bones to accommodate the increasing size of the brain. Therefore, the sutures between the bones of the cranial vault as well as growth plates in the skull base remain nonossified for an extensive period after birth. There are reports describing potential roles for TGF-βs in the differentiation of the membranous bones of the skull (Opperman et al., 1999), but there is no information concerning TGF-β function in the biology of the bones of the skull base. Histological studies of the sutures in wild-type and Ltbp-3– animals revealed no pathological synostosis, i.e. premature fusion of one or more of the cranial vault sutures (unpublished data). However, differential staining for cartilage and bone in whole mount preparations, as well as histological analysis of the cranial base in 21 day old animals, revealed that the cartilaginous growth plates of the synchondroses were absent in mutant animals (Fig. 3, B and D) , whereas the synchondroses were nonossified in wild-type littermates (Fig. 3, A and C).


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)

Histology of wild-type and Ltbp-3– skulls. (A and B) Fusion of bones of the skull base in 3-wk-old Ltbp-3 mice. Whole mount skulls of wild-type (A) and mutant (B) animals were stained with alcian blue for cartilage and Alizarin red S for calcified bone, and skull bases were dissected. Arrows point to synchondroses between occipital (oc), sphenoid (sp) and presphenoid (ps) bones. (C and D). Histology of the skull base of 3-wk-old wild-type (C) and Ltbp-3– (D) animals. Cartilage is stained red and bone blue. The basooccipital–basosphenoid synchondrosis is on the left.
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Related In: Results  -  Collection

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fig3: Histology of wild-type and Ltbp-3– skulls. (A and B) Fusion of bones of the skull base in 3-wk-old Ltbp-3 mice. Whole mount skulls of wild-type (A) and mutant (B) animals were stained with alcian blue for cartilage and Alizarin red S for calcified bone, and skull bases were dissected. Arrows point to synchondroses between occipital (oc), sphenoid (sp) and presphenoid (ps) bones. (C and D). Histology of the skull base of 3-wk-old wild-type (C) and Ltbp-3– (D) animals. Cartilage is stained red and bone blue. The basooccipital–basosphenoid synchondrosis is on the left.
Mentions: The appropriate anatomical development of the skull requires the coordinated growth of the membranous and endochondral bones to accommodate the increasing size of the brain. Therefore, the sutures between the bones of the cranial vault as well as growth plates in the skull base remain nonossified for an extensive period after birth. There are reports describing potential roles for TGF-βs in the differentiation of the membranous bones of the skull (Opperman et al., 1999), but there is no information concerning TGF-β function in the biology of the bones of the skull base. Histological studies of the sutures in wild-type and Ltbp-3– animals revealed no pathological synostosis, i.e. premature fusion of one or more of the cranial vault sutures (unpublished data). However, differential staining for cartilage and bone in whole mount preparations, as well as histological analysis of the cranial base in 21 day old animals, revealed that the cartilaginous growth plates of the synchondroses were absent in mutant animals (Fig. 3, B and D) , whereas the synchondroses were nonossified in wild-type littermates (Fig. 3, A and C).

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