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Hyaluronan Accumulation in Thyroid Tissue: Evidence for Contributions from Epithelial Cells and Fibroblasts

Divisions of Molecular Medicine (A.G.G., C.S.K., T.J.S.) and Endocrinology and Metabolism (A.G.G., T.J.S.), Harbor-UCLA Medical Center, Torrance, California 90502; the David Geffen School of Medicine at the University of California Los Angeles (A.G.G., T.J.S.), Los Angeles, California 90095; Department of Pathology (T.A.J., C.E.S.), Albany Medical College, Albany, New York 12208; the Veterans Affairs Medical Center (N.H.), Long Beach, California 90822; and the Ludwig Institute for Cancer Research Biomedical Center (P.H.), Uppsala S-75124, Sweden

Address all correspondence and requests for reprints to: Terry J. Smith, M.D., Division of Molecular Medicine, Building C-2, Harbor-UCLA Medical Center, Torrance, California 90502. E-mail: tjsmith{at}ucla.edu.

Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are autoimmune processes often associated with hyperthyroidism and hypothyroidism, respectively. Despite their diverging clinical presentations, immune activation drives both diseases and results in connective tissue accumulation of the nonsulfated glycosaminoglycan, hyaluronan. The hydrophilic property of hyaluronan contributes to the pathogenesis of thyroid-associated ophthalmopathy, dermopathy and hypothyroid myxedema. Whether hyaluronan accumulates in the thyroid and plays a role in goiter formation in GD and HT remains unknown. We report here that levels of hyaluronan are increased in thyroid tissue from individuals with both diseases compared with glands uninvolved with autoimmune disorders. The transcript encoding hyaluronan synthase (HAS)-3, one of three mammalian HAS isoforms, was detected in thyroid tissue. Isolated thyrocytes in primary culture express all three HAS isoforms when treated with IL-1ß. Thyrocytes and thyroid fibroblasts produce hyaluronan under basal culture conditions and IL-1ß enhances levels of this molecule in both cell types. On a per-cell basis, fibroblasts produce more hyaluronan than do thyrocytes under basal conditions and after cytokine treatment. Synthesis in thyrocytes can also be altered by increasing serum concentration in the medium and by modifying culture density. Our findings suggest that hyaluronan accumulation in thyroid tissue might derive from thyrocytes and fibroblasts. Moreover, this glycosaminoglycan becomes more abundant as a consequence of autoimmune disease. It may therefore contribute to increased thyroid volume in GD and HT. Coupled with the newly identified influence exerted by hyaluronan on immunocompetent cells, our findings represent potentially important insights into the pathogenesis of autoimmune thyroid diseases.