Thyroid functions of mouse cathepsins B, K, and L
Bianca Friedrichs, … , Paul Saftig, Klaudia Brix
Bianca Friedrichs, … , Paul Saftig, Klaudia Brix
Published June 1, 2003
Citation Information: J Clin Invest. 2003;111(11):1733-1745. https://doi.org/10.1172/JCI15990.
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Thyroid functions of mouse cathepsins B, K, and L

Abstract

Thyroid function depends on processing of the prohormone thyroglobulin by sequential proteolytic events. From in vitro analysis it is known that cysteine proteinases mediate proteolytic processing of thyroglobulin. Here, we have analyzed mice with deficiencies in cathepsins B, K, L, B and K, or K and L in order to investigate which of the cysteine proteinases is most important for proteolytic processing of thyroglobulin in vivo. Immunolabeling demonstrated a rearrangement of the endocytic system and a redistribution of extracellularly located enzymes in thyroids of cathepsin-deficient mice. Cathepsin L was upregulated in thyroids of cathepsin K–/– or B–/–/K–/– mice, suggesting a compensation of cathepsin L for cathepsin K deficiency. Impaired proteolysis resulted in the persistence of thyroglobulin in the thyroids of mice with deficiencies in cathepsin B or L. The typical multilayered appearance of extracellularly stored thyroglobulin was retained in cathepsin K–/– mice only. These results suggest that cathepsins B and L are involved in the solubilization of thyroglobulin from its covalently cross-linked storage form. Cathepsin K–/–/L–/– mice had significantly reduced levels of free thyroxine, indicating that utilization of luminal thyroglobulin for thyroxine liberation is mediated by a combinatory action of cathepsins K and L.

Authors

Bianca Friedrichs, Carmen Tepel, Thomas Reinheckel, Jan Deussing, Kurt von Figura, Volker Herzog, Christoph Peters, Paul Saftig, Klaudia Brix

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Alterations in thyroid physiological parameters. (a and b) Morphometric ...
Alterations in thyroid physiological parameters. (a and b) Morphometric analysis of epithelial extensions, i.e., cell heights (a), and follicle dimensions (b) of thyroids from WT and cathepsin-deficient mice. Extensions of thyroid epithelia were significantly reduced (a) whereas follicle areas were significantly increased (b) in mice of all cathepsin-deficient genotypes. (c and d) To determine whether flattening of epithelia reflects a reduction in the functional activities of thyroid glands, serum T4 levels were determined by a radiometric immunoassay. (c) The scatter graph indicates distribution of serum T4 levels plotted against mouse age. (d) Data from mice of all ages were analyzed. Serum T4 levels were significantly but slightly reduced in cathepsin L–/– mice (c and d, blue). A systemic defect in thyroid function was apparent from the very significantly reduced serum T4 levels in cathepsin K–/–/L–/– mice (c and d, cyan). Mean values ± SD are given in a and d, mean values ± SE in b. Lines represent linear regressions of the single data plotted against mouse age in c. *P < 0.05, **P < 0.01. In a and b, arbitrarily chosen follicles were analyzed; n = 162, 70, 71, 114, 150, and 58, respectively. In c and d, T4 levels of different animals were determined; n = 25, 12, 10, 14, 28, and 13, respectively.