title: Nucleosides accelerate inflammatory osteolysis, acting as distinct innate immune activators.
abstract: The innate immune system and its components play an important role in the pathogenesis of inflammatory bone destruction. Blockade of inflammatory cytokines does not completely arrest bone erosion, suggesting that other mediators also may be involved in osteolysis. Previously we showed that nucleosides promote osteoclastogenesis and bone-resorption activity in the presence of receptor activator for nuclear factor κB ligand (RANKL) in vitro. The studies described here further demonstrate that selected nucleosides and nucleoside analogues accelerate bone destruction in mice immunized with collagen II alone (CII) but also further enhance bone erosion in mice immunized by collagen II plus complete Freund's adjuvant (CII + CFA). Abundant osteoclasts are accumulated in destructive joints. These data indicate that nucleosides act as innate immune activators distinct from CFA, synergistically accelerating osteoclast formation and inflammatory osteolysis. The potential roles of the surface triggering receptor expressed on myeloid cells (TREM) and the intracellular inflammasome in nucleoside-enhanced osteoclastogenesis have been studied. These observations provide new insight into the pathogenesis and underlying mechanism of bone destruction in inflammatory autoimmune osteoarthritis.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, GA 30322, USA. zpan2@emory.edu
authors.forename: George
authors.initials: G
authors.lastname: Pan
authors.forename: Rui
authors.initials: R
authors.lastname: Zheng
authors.forename: Pingar
authors.initials: P
authors.lastname: Yang
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.forename: John P
authors.initials: JP
authors.lastname: Clancy
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Liu
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.forename: David A
authors.initials: DA
authors.lastname: Garber
authors.forename: Paul
authors.initials: P
authors.lastname: Spearman
authors.forename: Jay M
authors.initials: JM
authors.lastname: McDonald
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000276:immunology / Q000473:pathology; D001862:Bone Resorption / Q000150:complications / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D005269:Femur / Q000187:drug effects / Q000473:pathology; D007113:Immunity, Innate / Q000187:drug effects*; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009705:Nucleosides / Q000494:pharmacology*; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D011971:Receptors, Immunologic / Q000378:metabolism; D011983:Receptors, Purinergic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009705:Nucleosides; D011971:Receptors, Immunologic; D011983:Receptors, Purinergic