Members of the TGF-beta superfamily appear to modulate mesenchymal differentiation, including the processes of cartilage and bone formation. Nothing is yet known about the function of the TGF-beta-related factor vgr-1, also called bone morphogenetic protein-6 (BMP-6), and only limited studies have been conducted on the most closely related factors BMP-5, osteogenic protein-1 (OP-1) or BMP-7, and OP-2. Because vgr-1 mRNA has been localized in hypertrophic cartilage, this factor may play a vital role in endochondral bone formation. We developed antibodies to vgr-1, and documented that vgr-1 protein was expressed in hypertrophic cartilage of mice. To further characterize the role of this protein in bone differentiation, we generated CHO cells that overexpressed recombinant murine vgr-1 protein. Western blot analysis documented that recombinant vgr-1 protein was secreted into the media and was proteolytically processed to yield the mature vgr-1 molecule. To assess the biological activity of recombinant vgr-1 in vivo, we introduced the vgr-1-expressing CHO cells directly into the subcutaneous tissue of athymic nude mice. CHO-vgr-1 cells produced localized tumors, and the continuous secretion of vgr-1 resulted in tumors with a strikingly different gross and histological appearance as compared to the parental CHO cells. The tumors of control CHO cells were hemorrhagic, necrotic, and friable, whereas the CHO-vgr-1 tumors were dense, firm, and fibrotic. In contrast with control CHO tumors, the nests of CHO-vgr-1 tumor cells were surrounded by extensive connective tissue, which contained large regions of cartilage and bone. Further analysis indicated that secretion of vgr-1 from the transfected CHO tumor cells induced the surrounding host mesenchymal cells to develop along the endochondral bone pathway. These findings suggest that endochondral bone formation.
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15 September 1994
Article|
September 15 1994
Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral bone formation in vivo.
S E Gitelman,
S E Gitelman
Department of Pediatrics, University of California at San Francisco 94143.
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M S Kobrin,
M S Kobrin
Department of Pediatrics, University of California at San Francisco 94143.
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J Q Ye,
J Q Ye
Department of Pediatrics, University of California at San Francisco 94143.
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A R Lopez,
A R Lopez
Department of Pediatrics, University of California at San Francisco 94143.
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A Lee,
A Lee
Department of Pediatrics, University of California at San Francisco 94143.
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R Derynck
R Derynck
Department of Pediatrics, University of California at San Francisco 94143.
Search for other works by this author on:
S E Gitelman
Department of Pediatrics, University of California at San Francisco 94143.
M S Kobrin
Department of Pediatrics, University of California at San Francisco 94143.
J Q Ye
Department of Pediatrics, University of California at San Francisco 94143.
A R Lopez
Department of Pediatrics, University of California at San Francisco 94143.
A Lee
Department of Pediatrics, University of California at San Francisco 94143.
R Derynck
Department of Pediatrics, University of California at San Francisco 94143.
Online ISSN: 1540-8140
Print ISSN: 0021-9525
J Cell Biol (1994) 126 (6): 1595–1609.
Citation
S E Gitelman, M S Kobrin, J Q Ye, A R Lopez, A Lee, R Derynck; Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral bone formation in vivo.. J Cell Biol 15 September 1994; 126 (6): 1595–1609. doi: https://doi.org/10.1083/jcb.126.6.1595
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