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Orbital Fibroblast Heterogeneity May Determine the Clinical Presentation of Thyroid-Associated Ophthalmopathy

Division of Molecular Medicine (T.J.S.), Harbor-UCLA Medical Center, Torrance, California 90502, and School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; Cancer Center and Department of Microbiology and Immunology (L.K., G.D.S., R.P.P.), University of Rochester School of Medicine and Dentistry, Rochester, New York 14642; and Ottawa Health Research Institute and Departments of Medicine, Biochemistry, Microbiology, and Immunology (A.G., A.B., A.S.), University of Ottawa, Ottawa, Canada K1Y 4E9

Address all correspondence and requests for reprints to: Terry J. Smith, M.D., Division of Molecular Medicine, Building C-2, Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, California 90502. E-mail: tjsmith{at}ucla.edu

Thyroid-associated ophthalmopathy, a process in which the orbital tissues become inflamed and are remodeled, occurs with a variable presentation. In some patients, eye muscle enlargement predominates. In others, the connective/adipose tissue enlargement appears the more significant problem. Orbital fibroblasts exhibit heterogeneous phenotypes in culture. Here we report that fibroblasts derived from the connective/adipose tissue depot are distinct from those investing the extraocular muscles. Connective tissue fibroblasts represent a bimodal population of cells with regard to the surface display of the glycoprotein, Thy-1. Perimysial fibroblasts in contrast express Thy-1 uniformly. In that regard, they resemble those from the skin. When subjected to a newly defined set of culture conditions, adipocyte differentiation occurs in up to 43% of the cells. All adipocytes examined failed to display Thy-1. Fibroblasts derived from perimysium and dermis uniformly do not differentiate into adipocytes when incubated under identical culture conditions. Both Thy-1⁺ and Thy-1^- connective tissue fibroblasts express the adipogenic trigger, peroxisome proliferator activator , suggesting that differences in the potential for differentiation may reside with phenotypic attributes downstream from this receptor/adipogenic transcription factor. These observations enhance our understanding of orbital adipogenesis and define previously unrecognized differences between fibroblasts from the extraocular muscle and connective tissue.

Present address for G.D.S.: Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710.

This work was supported in part by NIH Grants EY08976, EY11708, DE11390, H150002, and ES01247; a Merit Review award from Research Service of the Department of Veterans Affairs; Heart and Stroke Foundation of Canada Grant T-4740. A.G. was supported by a CDA postdoctoral research award. A.B. was supported by a CIHR/HSFC doctoral research award. A.S. is a Career Investigator of the Heart and Stroke Foundation of Ontario.

Abbreviations: cPGI₂, Carbaprostacyclin; HRP, horseradish peroxidase; IBMX, isobutylmethylxanthone; RT, room temperature; TAO, thyroid-associated ophthalmopathy; TSHr, TSH receptor.

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