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Latent Forms of Transforming Growth Factor-β (TGFβ) Derived from Bone Cultures: Identification of a Naturally Occurring 100-kDa Complex with Similarity to Recombinant Latent TGFβ

Department of Medicine, Division of Endocrinology and Metabolism, University of Texas Health Science Center San Antonio, Texas 78284–7877
National Cancer Institute, National Institutes of Health Bethesda, Maryland 20892
Bristol-Meyers/Squibb Seattle, Washington 98121

Address requests for reprints to: Dr. Lynda F. Bonewald, Department of Medicine, Division of Endocrinology and Metabolism, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7877.

Abstract

Transforming growth factor-β (TGFβ) is produced by most tissues, including bone, as a complex that is biologically inert. Release of TGFβ homodimer from this latent complex is necessary for TGFβ to exert effects on target cells. Thus, the nature of the latent complex and the mechanisms responsible for TGFβ release are the key to understanding TGFβ actions. We have found that murine calvarial bone cultures secrete multiple latent forms of TGFβ. Using analytical chromatography and Western blot analysis, we have compared bone latent TGFβ with the previously characterized latent complex present in platelets and with simian TGFβ precursor, which is stably expressed in a latent form by Chinese hamster ovarian (CHO) cells. A major component of the bone material appears to be a latent complex of 100 kDa, consisting of mature TGFβ (25-kDa homodimer) noncovalently associated with the remainder of the TGFβ precursor proregion (75-kDa homodimer). Like the recombinant TGFβ precursor, it elutes from a Mono-Q fast pressure liquid chromatography anion exchange column at 0.2 M NaCI and shows a very similar banding pattern on Western blots. Thus, this bone complex closely resembles recombinant TGFβ precursor expressed in a latent form by CHO cells and differs from the naturally occurring platelet complex, which has an additional 135-kDa binding protein that is bound through disulfide bonds to the precursor proregion. Western blot analysis also indicates that, like CHO cells, which express recombinant TGFβ precursor, but unlike other cell types, the bone cultures secrete detectable amounts of uncleaved TGFβ precursor. The bone calvarial culture is the first example of a naturally occurring system that expresses the 100-kDa latent TGFβ complex.

FOOTNOTES

This work was supported by Grants AR-39357, DE-08569, AR-39529, and AR-07464 from the NIH.

Received for publication December 17, 1990. Revision received February 14, 1991. Accepted for publication March 12, 1991.

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