TNF-alpha antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is associated with focal and systemic bone loss involving cytokines such as RANKL and TNF-alpha. RANK-L promotes focal and systemic osteoporosis, whereas osteoprotegerin (OPG) inhibits bone resorption. Although anti-TNF-alpha antibodies (anti-TNF-alpha Ab) decrease joint inflammation and bone erosions, their effects on bone loss are unknown. The aim of this study was to evaluate the effects of OPG and anti-TNF-alpha Ab, separately or in combination, on inflammation and bone remodeling in collagen-induced arthritis (CIA), a model of RA.


METHODS
DBA/1 mice (n=28) were immunized with bovine type II collagen and treated with OPG-Fc or anti-TNF-alpha Ab or both, or saline. One group of mice (n=7) was not immunized (naive group). Urinary deoxypyridinoline (D-pyr) and whole-body bone mineral density (BMD) were measured at baseline and at sacrifice. Histomorphometric parameters were evaluated at the femoral metaphysis.


RESULTS
Anti-TNF-alpha Ab, but not OPG, decreased the clinical arthritis score (P<0.02 vs. saline) and the histological score of inflammation. The BMD change from baseline to sacrifice (DeltaBMD) was significantly smaller in CIA mice than naive mice. OPG and anti-TNF-alpha Ab significantly increased DeltaBMD versus saline, and the effect was greater with OPG (P<0.003). DeltaD-pyr decreased by 65% with OPG and 13% with anti-TNF-alpha Ab. Compared with saline, OPG increased trabecular bone volume (BV/TV) (P<0.02), decreased trabecular separation (P<0.02), and decreased the bone formation rate (BFR) (P<0.01). Anti-TNF-alpha Ab produced no significant changes in bone volume or trabecular separation but increased trabecular thickness (P<0.02 vs. saline) to a value close to that in naive mice, suggesting preservation of bone formation. No additive effects of OPG and anti-TNF-alpha Ab were found.


CONCLUSIONS
Systemic OPG and anti-TNF-alpha Ab therapy prevented bone loss in CIA mice through distinct mechanisms involving decreased bone resorption and preserved bone formation. Combining these two agents might help to prevent bone loss in inflammatory diseases.
Saidenberg-Kermanac'h
N
N
UPRES EA-3408 and Department of Rheumatology, Avicenne Hospital (AP-HP), Claude Bernard Foundation, Bobigny Medical School, Paris 13 University, Paris, France. nathalie.saidenberg@avc.ap-hop-paris.fr
Corrado
A
A
Lemeiter
D
D
deVernejoul
M C
MC
Boissier
M C
MC
Cohen-Solal
M E
ME
D000596:Amino Acids / Q000652:urine; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy* / Q000209:etiology; D005269:Femur / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D006023:Glycoproteins / Q000494:pharmacology*; D007249:Inflammation / Q000150:complications* / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
D000596:Amino Acids; D000906:Antibodies; D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506031:Tnfrsf11b protein, mouse; D014409:Tumor Necrosis Factor-alpha; C036020:deoxypyridinoline