Function of Cathepsin K in the Central Nervous System of Male Mice is Independent of Its Role in the Thyroid Gland

Abstract

Cathepsin K deficiency in male mice (Ctsk−/−) results in decreased numbers of hippocampal astrocytes and altered neuronal patterning as well as learning and memory deficits. Additionally, cathepsin K carries essential roles in the thyroid gland where it contributes to the liberation of thyroid hormones (TH). Because TH are essential for brain development, in particular for the cerebellum, we investigated whether cathepsin K’s function in the thyroid is directly linked to the brain phenotype of Ctsk−/− mice. Serum levels of thyroid stimulating hormone, brain concentrations of free TH, and deiodinase 2 (Dio2) activity in brain parenchyma as well as cerebellar development were comparable in Ctsk−/− and WT animals, suggesting regular thyroid states and TH metabolism. Despite unaltered transcript levels, protein expression of two TH transporters was enhanced in specific brain regions in Ctsk−/− mice, suggesting altered TH supply to these regions. Thyrotropin releasing hormone (Trh) mRNA levels were enhanced threefold in the hippocampus of Ctsk−/− mice. In the striatum of Ctsk−/− mice the mRNA for Dio2 and hairless were approximately 1.3-fold enhanced, while mRNA levels for monocarboxylate transporter 8 and Trh were reduced to 60% and 40%, respectively, pointing to altered striatal physiology. We conclude that the role of cathepsin K in the thyroid gland is not directly associated with its function in the central nervous system (CNS) of mice. Future studies will show whether the brain region-specific alterations in Trh mRNA may eventually result in altered neuroprotection that could explain the neurobehavioral defects of Ctsk−/− mice.

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Acknowledgements

The authors are grateful to Prof. Dr. Paul Saftig, Institute of Biochemistry, Christian-Albrechts-Universität Kiel, Germany, for providing the cathepsin K-deficient mouse model. We would like to thank Thomas Ströhlein for professional help in the transgenic animal facility at Jacobs University.

A previous version of this study was included as manuscript chapter in the publicly available dissertation of S.D. (https://opus.jacobs-university.de/frontdoor/index/index/docId/75). A modified version of Figs. 1 and 2f was included in the dissertation of J.W. (https://opus.jacobs-university.de/frontdoor/index/index/docId/548).

Funding

This study was supported by Jacobs University Bremen, Germany, Projects 2140/90402 and 6113/90140 to KB, and by the Research Centers AgeAct and MOLIFE; SD and RS received a stipend from the Department of Life Sciences and Chemistry, then, School of Engineering and Science, Jacobs University Bremen, Germany. The study was further supported by Deutsche Forschungsgemeinschaft, Bonn, Germany, in the framework of the SPP1629, BR 1308/11-1 and 11-2 to KB, FU 356/7-1 and 7-2 to DF, Schw 914/4-1 to US, WI 3768/2-1 to EW and US, and EW was further supported by WI 3768/1-1.

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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by SD, HR, RS, II, JW, BBD, DB, MR, EW, DF, US and KB. The first draft of the manuscript was written by SD and KB and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Klaudia Brix.

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All procedures performed in studies involving animals were conducted in accordance with institutional guidelines in S1-laboratories of Jacobs University Bremen (Senator für Arbeit, Frauen, Gesundheit, Jugend und Soziales der Hansestadt Bremen Az. 513-30-00/2-15-32 including KB as project leader, and Az. 0515_2040_15 to KB allowing breeding, housing and sacrifice of genetically engineered mice).

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Dauth, S., Rakov, H., Sîrbulescu, R.F. et al. Function of Cathepsin K in the Central Nervous System of Male Mice is Independent of Its Role in the Thyroid Gland. Cell Mol Neurobiol 40, 695–710 (2020). https://doi.org/10.1007/s10571-019-00765-6

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Keywords

  • Cathepsin K
  • Thyroid gland function
  • Thyroid hormone transporters
  • Thyroid hormone target genes
  • Brain function