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J Biol Chem, Vol. 275, Issue 8, 5860-5866, February 25, 2000

The Insulin-like Growth Factors (IGFs) I and II Bind to Articular Cartilage via the IGF-binding Proteins^*

Nirav R. Bhakta, A. Minerva Garcia, Eliot H. Frank, Alan J. Grodzinsky, and Teresa I. Morales^§¶

From the  Center for Biomedical Engineering and Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 and the ^§ Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Bovine articular cartilage discs (3 mm diameter × 400 µm thick) were equilibrated in buffer containing ¹²⁵I-insulin-like growth factor (IGF)-I (4 °C) ± unlabeled IGF-I or IGF-II. Competition for binding to cartilage discs by each unlabeled IGF was concentration-dependent, with ED₅₀ values for inhibition of ¹²⁵I-IGF-I binding of 11 and 10 nM for IGF-I and -II, respectively, and saturation by 50 nM. By contrast, an analog of IGF-I with very low affinity for the insulin-like growth factor-binding proteins (IGF-BPs), des-(1-3)-IGF-I, was not competitive with ¹²⁵I-IGF-I for cartilage binding even at 100-400 nM. Binding of the ¹²⁵I-labeled IGF-II isoform to cartilage was competed for by unlabeled IGF-I or -II, with ED₅₀s of 160 and 8 nM, respectively. This probably reflected the differential affinities of the endogenous IGF-BPs (IGF-BP-6 and -2) for IGF-II/IGF-I. Transport of ¹²⁵I-IGF-I was also measured in an apparatus that allows diffusion only across the discs (400 µm), by addition to one side and continuous monitoring of efflux on the other side. The time lag for transport of ¹²⁵I-IGF was 266 min, an order of magnitude longer than the theoretical prediction for free diffusion in the matrix. ¹²⁵I-IGF-I transport then reached a steady state rate (% efflux of total added ¹²⁵I-IGF/unit time), which was subsequently accelerated ~2-fold by addition of an excess of unlabeled IGF-I. Taken together, these results indicate that IGF binding to cartilage, mostly through the IGF-BPs, regulates the transport of IGFs in articular cartilage, probably contributing to the control of their paracrine activities.

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