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* Department of Anti-Aging Orthopedic Research,
Department of Orthopedic Surgery,
Department of Pathology, and
Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan;
¶ Department of Orthopedics, Kyoto University, Konoe-cho, Yoshida Sakyo-ku, Kyoto, Japan; and
|| Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Caspary Research Building, New York, NY 10021
The TNF-
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.
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1 This work was supported by The Uehara Memorial Foundation, The Mochida Memorial Foundation, and Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (19591765) to K.H.
2 Address correspondence and reprint requests to Dr. Keisuke Horiuchi, Department of Orthopedic Surgery, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan. E-mail address: horiuchi{at}z3.keio.jp
3 Abbreviations used in this paper: TACE, TNF- converting enzyme; ADAM17, a disintegrin and metalloprotease 17; EGFR, epidermal growth factor receptor; MPO, myeloperoxidase; vWF, von Willebrand factor; sKitL, soluble c-Kit ligand; KSL, c-Kit-1+ Sca-1+ lineage–.
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  K. Horiuchi, H. Morioka, H. Takaishi, H. Akiyama, C. P. Blobel, and Y. Toyama Ectodomain Shedding of FLT3 Ligand Is Mediated by TNF-{alpha} Converting Enzyme J. Immunol., June 15, 2009; 182(12): 7408 - 7414. [Abstract] [Full Text] [PDF]
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