title: Osteoclast precursors: cytokine-stimulated immunomodulators of inflammatory bone disease.
abstract: OBJECTIVE
  Proinflammatory cytokines produced in inflamed joints promote the generation and release from the bone marrow of osteoclast precursors (OCPs). These OCPs are recruited to inflamed joints where, in response to proinflammatory cytokines, they differentiate into osteoclasts and behave as immunomodulatory cells. We review the regulation of OCP formation and differentiation, and propose that they are not only sources of bone-resorbing osteoclasts, but also of immune cells that influence the progression of inflammatory bone diseases.
  
  
  RESULTS
  OCP numbers are increased in the blood of humans and animals with tumor necrosis factor (TNF)-mediated arthritis and they correlate with serum TNF levels, which can be lowered by anti-TNF therapy. TNF stimulates bone marrow OCP generation in part by increasing their expression of c-Fms. These precursors then leave the bone marrow and circulate in the blood stream. Receptor activator NF-kappaB ligand (RANKL) and TNF, which are elevated in inflamed joints, mediate OCP differentiation into osteoclasts and other cell types, including dendritic cells. They also stimulate OCPs to produce proinflammatory cytokines and chemokines. RANKL inhibition prevents joint inflammation in TNF-mediated arthritis.
  
  
  CONCLUSIONS
  OCPs are effector immunomodulatory cells in inflammatory bone diseases. They respond to and secrete cytokines, and are therefore targets for anti-inflammatory therapy.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA. brendan_boyce@urmc.rochester.edu
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
mesh_terms: D001847:Bone Diseases / Q000276:immunology* / Q000503:physiopathology*; D002454:Cell Differentiation; D016207:Cytokines / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology*; D008954:Models, Biological; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology / Q000502:physiology
chemical_list: D016207:Cytokines; D007155:Immunologic Factors