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The Effect of Cell-Matrix Interaction on Parathyroid Hormone (PTH) Receptor Binding and PTH Responsiveness in Proximal Renal Tubular Cells and Osteoblast-Like Cells¹

Divisions of Nephrology and Endocrinology, Department of Medicine, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Jacob Green, M.D., Department of Nephrology, Rambam Medical Center, Haifa 31096, Israel. E-mail: greeny{at}rambam.health.gov.il

The interaction of cells with the surrounding extracellular matrix (ECM) or basement membrane (BM) brings about profound changes in cellular biological responses, such as cell differentiation, proliferation, and gene expression. We studied the effect of ECM on PTH receptor binding and on biological responses mediated by PTH, in two cell preparations: 1) the proximal tubular OK opossum kidney cell line; and 2) MC₃T₃-E₁ cells, a clonal line of nontransformed murine osteoblasts. Cells were plated on either plastic surfaces or on tissue culture dishes coated with specific ECM components. In both cell types plated on collagen-type IV (Col-IV), PTH receptor binding, on day 4 of culture, was markedly diminished, when compared with cells on plastic (approximately 45% inhibition, P < 0.01). In addition, Col-IV dose dependently inhibited cAMP generation stimulated by PTH (P < 0.001 vs. plastic), whereas cAMP generation by PGE₂, cholera toxin, and forskolin was not altered. In Northern blot analysis, a PTH/PTH-related-protein receptor messenger RNA transcript was detected in both the kidney and bone cells. However, only OK cells manifested a decreased abundance of receptor messenger RNA when plated on Col-IV, compared with plastic. The physiological significance of inhibited cAMP production by Col-IV was evaluated by measuring the influence of different matrices on the activity of Na⁺/H⁺ exchanger (NHE) in OK cells and cell mitogenic activity in MC₃T₃-E₁ cells (both responses are negatively modulated by cAMP). OK cells plated on Col-IV showed 70% inhibition of NHE, compared with cells plated on plastic (P < 0.01). PTH inhibits NHE activity in cells on plastic but stimulates exchanger activity by 40% in cells plated on Col-IV. In MC₃T₃-E₁ cells grown on plastic, PTH exerts a dose- dependent antiproliferative effect, which is mediated by cAMP. This effect is mitigated when cells are grown on Col-IV (40–50% less antiproliferative effect). In summary, Col-IV, a major BM constituent, has a profound inhibitory effect on PTH binding and PTH-mediated biological responses in both kidney tubular cells and osteoblasts. Altered cellular function by Col-IV may be of physiological relevance in states associated with altered composition of BM or expansion of ECM (e.g. diabetes mellitus and interstitial fibrosis).

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