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Potential Mechanisms for the Plasmin-Mediated Release and Activation of Latent Transforming Growth Factor-ß1 from the Extracellular Matrix of Growth Plate Chondrocytes¹

Departments of Orthopaedics (H.A.P., Z.S., M.R., R.G., D.D.D., B.D.B.), Periodontics (Z.S., B.D.B.), Biochemistry (L.F.B., B.D.B.), and Medicine (L.F.B.), The University of Texas Health Science Center, San Antonio, Texas 78229-3900; and Department of Periodontics (Z.S.), Hebrew University, Hadassah Faculty of Dental Medicine, Jerusalem, Israel 91010

Address all correspondence and requests for reprints to: Barbara D. Boyan, Ph.D., Department of Orthopaedics (7774), The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900. E-mail: BoyanB{at}uthscsa.edu

Chondrocytes produce latent transforming growth factor-ß1 (TGF-ß1) in a small, circulating form of 100 kDa and also store latent TGF-ß1 in their matrix in a large form of 290 kDa containing the latent TGF-ß1 binding protein 1. As growth plate cartilage cells are exceptionally sensitive to TGF-ß1 and are known to produce plasminogen activator, the role of plasmin in the activation of soluble and matrix-bound latent TGF-ß1 was examined. As is true for other cell types, low-dose plasmin (0.01 U/ml) was found to release both active and latent TGF-ß1 from chondrocyte matrix in a time-dependent manner over 3 h. However, high-dose plasmin (1.0 U/ml) was found to release active TGF-ß1 more rapidly than low-dose plasmin, and this release ceased within 30 min; latent complex continued to be released over time (3 h). When high-dose plasmin was titrated against the serine protease inhibitors, aprotinin and -(2-aminoethyl)benzenesulfonyl fluoride, results similar to low-dose plasmin were obtained, indicating that the effects of high-dose plasmin could be altered to mimic those of low-dose plasmin. No differences were observed on the effects of plasmin on the release of TGF-ß1 from the matrices of either growth zone or resting zone chondrocytes.

We examined whether plasmin could further activate the truncated large latent TGF-ß1 complex of 230 kDa that was released into the media by plasmin. It is known that plasmin will activate the small latent complex, so this was compared with the truncated form. Plasmin completely activated the small latent complex, whereas a smaller, but significant, activation of the truncated form of latent TGF-ß1 also occurred. These studies may have relevance to normal physiological conditions, where plasminogen and/or plasmin is present in very small amounts in the cartilage and, therefore, small amounts of active TGF-ß1 would be present, and to pathological conditions such as fractures, where chondroprogenitor cells would be exposed to high concentrations of plasmin and, therefore, to short-term high concentrations of this potent chondrogenic growth factor.

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