Conditional inactivation of TACE by a Sox9 promoter leads to osteoporosis and increased granulopoiesis via dysregulation of IL-17 and G-CSF.
The TNF-alpha 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.
Horiuchi
Keisuke
K
Department of Anti-Aging Orthopedic Research, Keio University, School of Medicine, Shinjuku-ku, Tokyo, Japan. horiuchi@z3.keio.jp
Kimura
Tokuhiro
T
Miyamoto
Takeshi
T
Miyamoto
Kana
K
Akiyama
Haruhiko
H
Takaishi
Hironari
H
Morioka
Hideo
H
Nakamura
Takashi
T
Okada
Yasunori
Y
Blobel
Carl P
CP
Toyama
Yoshiaki
Y
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D015502:Absorptiometry, Photon; D000818:Animals; D015153:Blotting, Western; D001842:Bone and Bones / Q000473:pathology / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D010024:Osteoporosis / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D055758:SOX9 Transcription Factor / Q000235:genetics*
D020381:Interleukin-17; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse