title: In vivo RANK signaling blockade using the receptor activator of NF-kappaB:Fc effectively prevents and ameliorates wear debris-induced osteolysis via osteoclast depletion without inhibiting osteogenesis.
abstract: Prosthesis failure due to wear debris-induced osteolysis remains a major clinical problem and the greatest limitation for total joint arthroplasty. Based on our knowledge of osteoclast involvement in this process and the requirements of receptor activator of NF-kappaB (RANK) signaling in osteoclastogenesis and bone resorption, we investigated the efficacy of RANK blockade in preventing and ameliorating titanium (Ti)-induced osteolysis in a mouse calvaria model. Compared with placebo controls we found that all doses of RANK:Fc above 1 mg/kg intraperitoneally (ip) per 48 h significantly inhibited osteoclastogenesis and bone resorption in response to Ti implanted locally. Complete inhibition occurred at 10 mg/kg ip per 48 h, yielding results that were statistically equivalent to data obtained with Ti-treated RANK-/- mice. We also evaluated the effects of a single injection of RANK:Fc on day 5 on established osteolysis and found that Ti-treated were still depleted for multinucleated tartrate-resistant acid phosphatase-positive (TRAP+) cells 16 days later. More importantly, this osteoclast depletion did not affect bone formation because the bone lost from the osteolysis on day 5 was restored by day 21. An assessment of the quantity and quality of the newly formed bone in these calvariae by calcein labeling and infrared (IR) microscopy, respectively, showed no significant negative effect of RANK:Fc treatment. These studies indicate that osteoclast depletion via RANK blockade is an effective method to prevent and reverse wear debris-induced osteolysis without jeopardizing osteogenesis.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, New York 14642, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Childs
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Paschalis
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
authors.forename: William C
authors.initials: WC
authors.lastname: Dougall
authors.forename: Dirk
authors.initials: D
authors.lastname: Anderson
authors.forename: Adele L
authors.initials: AL
authors.lastname: Boskey
authors.forename: J Edward
authors.initials: JE
authors.lastname: Puzas
authors.forename: Randy N
authors.initials: RN
authors.lastname: Rosier
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001857:Bone Matrix / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D006023:Glycoproteins / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008808:Mice, Inbred CBA; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D010014:Osteolysis; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D012886:Skull; D014025:Titanium / Q000494:pharmacology
chemical_list: D005452:Fluoresceins; D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506031:Tnfrsf11b protein, mouse; D014025:Titanium; D000135:Acid Phosphatase; C007740:fluorexon