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. © 2011 American Society for Bone and Mineral Research.

Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo

“…ADAM-8 (a disintegrin and metalloproteinase-8), which is highly expressed at the late stage of OCgenesis [28], is required for the fusion between osteoclast precursors and their differentiation in vitro and in vivo [29]. ADAM (also known as the adamalysin family) is a family of peptidase proteins [30] and is classified as sheddase based on the ability to cut off or shed extracellular portions of transmembrane proteins [31].…”

ISG15 Regulates RANKL-Induced Osteoclastogenic Differentiation of RAW264 Cells

“…This result is somewhat enigmatic, as the expression of both DC-STAMP and ATP6v0d2 is regulated by the same transcription factor NFATc1. 21,22) However, it is possible that ISG15 affects the factor(s) responsible for the regulation of ATP6v0d2 expression.…”

Prognostic and clinical implication of a disintegrin and metalloprotease 8 expression in pediatric medulloblastoma

“…ADAM8 gene encodes a protein of 824 amino acids with a carboxyterminal transmembrane domain and extracellular adhesion and protease domains [6]. It was initially cloned from monocytic cells and its expression has been found in neurons, reactive glia cells (astrocytes and microglia), and oligodendrocytes of central nervous system [7]. ADAM8 is implicated in bone morphogenesis and allergic inflammatory processes [8].…”