title: ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Medicine/Hematology-Oncology and the Center for Bone Biology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Hisako
authors.initials: H
authors.lastname: Ishizuka
authors.forename: Verónica
authors.initials: V
authors.lastname: García-Palacios
authors.forename: Ganwei
authors.initials: G
authors.lastname: Lu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Subler
authors.forename: Heju
authors.initials: H
authors.lastname: Zhang
authors.forename: Christina S
authors.initials: CS
authors.lastname: Boykin
authors.forename: Sun Jin
authors.initials: SJ
authors.lastname: Choi
authors.forename: Liena
authors.initials: L
authors.lastname: Zhao
authors.forename: Kenneth
authors.initials: K
authors.lastname: Patrene
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Galson
authors.forename: Harry C
authors.initials: HC
authors.lastname: Blair
authors.forename: Tamer M
authors.initials: TM
authors.lastname: Hadi
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Kurihara
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001862:Bone Resorption / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002459:Cell Fusion; D004789:Enzyme Activation / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C499636:DC-STAMP protein, mouse; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D051722:ADAM Proteins; C489402:Adam8 protein, mouse