Conditional inactivation of TACE by a Sox9 promoter leads to osteoporosis and increased granulopoiesis via dysregulation of IL-17 and G-CSF

Keisuke Horiuchi, Tokuhiro Kimura, Takeshi Miyamoto, Kana Miyamoto, Haruhiko Akiyama, Hironari Takaishi, Hideo Morioka, Takashi Nakamura, Yasunori Okada, Carl P. Blobel, Yoshiaki Toyama

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Abstract

The TNF-α converting enzyme (TACE/ADAM17) is involved in the proteolytic release of the ectodomain of diverse cell surface proteins with critical roles in development, immunity, and hematopoiesis. As the perinatal lethality of TACE-deficient mice has prevented an analysis of the roles of TACE in adult animals, we generated mice in which floxed Tace alleles were deleted by Cre recombinase driven by a Sox9 promoter. These mutant mice survived up to 9-10 mo, but exhibited severe growth retardation as well as skin defects and infertility. The analysis of the skeletal system revealed shorter long bones and prominent bone loss, characterized by an increase in osteoclast and osteoblast activity. In addition, these mice exhibited hypercellularity in the bone marrow and extramedullary hematopoiesis in the spleen and liver. Flow cytometric analysis of the bone marrow cells showed a sharp increase in granulopoiesis and in the population of c-Kit-1+ Sca-1+ lineage- cells, and a decrease in lymphopoiesis. Moreover, we found that serum levels of IL-17 and G-CSF were significantly elevated compared with control littermates. These findings indicate that TACE is associated with a regulation of IL-17 and G-CSF expression in vivo, and that the dysregulation in G-CSF production is causally related to both the osteoporosis-like phenotype and the defects in the hematopoietic system.

Original languageEnglish
Pages (from-to)2093-2101
Number of pages9
JournalJournal of Immunology
Volume182
Issue number4
DOIs
Publication statusPublished - 2009 Feb 15

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Horiuchi, K., Kimura, T., Miyamoto, T., Miyamoto, K., Akiyama, H., Takaishi, H., Morioka, H., Nakamura, T., Okada, Y., Blobel, C. P., & Toyama, Y. (2009). Conditional inactivation of TACE by a Sox9 promoter leads to osteoporosis and increased granulopoiesis via dysregulation of IL-17 and G-CSF. Journal of Immunology, 182(4), 2093-2101. https://doi.org/10.4049/jimmunol.0802491