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Thyrotropin receptor activation increases hyaluronan production in preadipocyte fibroblasts: Contributory role in hyaluronan accumulation in thyroid dysfunction

Zhang, Lei, Bowen, Timothy, Grennan-Jones, Fiona Antoinette, Paddon, Carol Ann, Giles, Peter James, Webber, Jason P., Steadman, Robert and Ludgate, Marian Elizabeth 2009. Thyrotropin receptor activation increases hyaluronan production in preadipocyte fibroblasts: Contributory role in hyaluronan accumulation in thyroid dysfunction. Journal of Biological Chemistry 284 (39) , pp. 26447-26455. 10.1074/jbc.M109.003616

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Abstract

The thyrotropin receptor (TSHR) is expressed during lineage-specific differentiation (e.g. adipogenesis) and is activated by TSH, thyroid-stimulating antibodies, and gain-of-function mutations (TSHR*). Comparison of gene expression profiles of nonmodified human preadipocytes (n = 4) with the parallel TSHR* population revealed significant up-regulation of 27 genes including hyaluronan (HA) synthases (HAS) 1 and 2. The array data were confirmed by quantitative PCR of HAS1 and HAS2 and enzyme-linked immunosorbent assay measurement of HA; all values were significantly increased (p < 0.03) in TSHR*-expressing preadipocytes (n = 10). Preadipocytes (n = 8) treated with dibutyryl (db)-cAMP display significantly increased HAS1 and HAS2 transcripts, HAS2 protein, and HA production (p < 0.02). HAS1 or HAS2 small interfering RNA treatment of db-cAMP-stimulated preadipocytes (n = 4) produced 80% knockdown in HAS1 or 61% knockdown in HAS2 transcripts (compared with scrambled), respectively; the corresponding HA production was reduced by 49 or 38%. Reporter assays using A293 cells transfected with HAS1 promoter-driven plasmids containing or not containing the proximal CRE and treated with db-cAMP revealed that it is functional. Chromatin immunoprecipitation, using a cAMP-responsive element-binding protein antibody, of db-cAMP-treated preadipocytes (n = 4) yielded products for HAS1 and HAS2 with relative fold increases of 3.3 ± 0.8 and 2.6 ± 0.9, respectively. HA accumulates in adipose/connective tissues of patients with thyroid dysfunction. We investigated the contributions of TSH and thyroid-stimulating antibodies and obtained small (9–24%) but significant (p < 0.02) increases in preadipocyte HA production with both ligands. Similar results were obtained with a TSHR monoclonal antibody lacking biological activity (p < 0.05). We conclude that TSHR activation is implicated in HA production in preadipocytes, which, along with thyroid hormone level variation, explains the HA overproduction in thyroid dysfunction.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > RC Internal medicine
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Funders: Wellcome Trust
Last Modified: 07 Mar 2019 22:07
URI: http://orca-mwe.cf.ac.uk/id/eprint/25247

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