ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo

Autor: Harry C. Blair, Tamer M Hadi, Jolene J. Windle, Verónica García-Palacios, Christina S. Boykin, Noriyoshi Kurihara, G. David Roodman, Ganwei Lu, Deborah L. Galson, Heju Zhang, Sun Jin Choi, Hisako Ishizuka, Kenneth D. Patrene, Liena Zhao, Mark A. Subler
Rok vydání: 2010
Předmět:
Endocrinology
Diabetes and Metabolism
Cellular differentiation
Osteoclasts
Cell Count
CELL DIFFERENTIATION
Bone remodeling
Cell Fusion
Mice
0302 clinical medicine
Fibrosis
Orthopedics and Sports Medicine
OSTEOCLAST
0303 health sciences
Stem Cells
NF-kappa B
Organ Size
Cell biology
Isoenzymes
src-Family Kinases
medicine.anatomical_structure
030220 oncology & carcinogenesis
Original Article
Mitogen-Activated Protein Kinases
ADAM8
Signal Transduction
musculoskeletal diseases
Genetically modified mouse
Acid Phosphatase
Mice
Transgenic
Nerve Tissue Proteins
Biology
Bone and Bones
ADHESION MOLECULES
03 medical and health sciences
Antigens
CD
In vivo
Osteoclast
medicine
Animals
Bone Resorption
Protein kinase B
030304 developmental biology
Tartrate-Resistant Acid Phosphatase
Tumor Necrosis Factor-alpha
RANK Ligand
Membrane Proteins
TRANSGENIC/KNOCKOUT MICE
medicine.disease
Enzyme Activation
ADAM Proteins
Immunology
Proto-Oncogene Proteins c-akt
Biomarkers
Zdroj: Journal of Bone and Mineral Research
ISSN: 0884-0431
Popis: ADAM8 expression is increased in the interface tissue around a loosened hip prosthesis and in the pannus and synovium of patients with rheumatoid arthritis, but its potential role in these processes is unclear. ADAM8 stimulates osteoclast (OCL) formation, but the effects of overexpression or loss of expression of ADAM8 in vivo and the mechanisms responsible for the effects of ADAM8 on osteoclastogenesis are unknown. Therefore, to determine the effects of modulating ADAM expression, we generated tartrate-resistant acid phosphatase (TRAP)–ADAM8 transgenic mice that overexpress ADAM8 in the OCL lineage and ADAM8 knockout (ADAM8 KO) mice. TRAP-ADAM8 mice developed osteopenia and had increased numbers of OCL precursors that formed hypermultinucleated OCLs with an increased bone-resorbing capacity per OCL. They also had an enhanced differentiation capacity, increased TRAF6 expression, and increased NF-κB, Erk, and Akt signaling compared with wild-type (WT) littermates. This increased bone-resorbing capacity per OCL was associated with increased levels of p-Pyk2 and p-Src activation. In contrast, ADAM8 KO mice did not display a bone phenotype in vivo, but unlike WT littermates, they did not increase RANKL production, OCL formation, or calvarial fibrosis in response to tumor necrosis factor α (TNF-α) in vivo. Since loss of ADAM8 does not inhibit basal bone remodeling but only blocks the enhanced OCL formation in response to TNF-α, these results suggest that ADAM8 may be an attractive therapeutic target for preventing bone destruction associated with inflammatory disease. © 2011 American Society for Bone and Mineral Research.
Databáze: OpenAIRE
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