Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis.
OBJECTIVE
To characterize bone microarchitectural changes and to test the hypothesis that disrupting local cytokine equilibrium could modify cartilage degradation in a murine model of experimental osteoarthritis (OA).


METHODS
Ten-week-old male C57BL/6 mice underwent medial meniscectomy of their right knees and a sham operation of their left knees. The mice received intraperitoneal injections of osteoprotegerin (OPG) (10 mg/kg), interleukin-1 receptor antagonist (IL-1Ra) (100 mg/kg), or phosphate buffered saline for 6 weeks. The microarchitecture of the trabecular bone, the OA score, and expression of ADAMTS-4 and ADAMTS-5 were assessed. Proteoglycan release was measured in cartilage explant cultures in the presence of IL-1Ra and OPG.


RESULTS
In the meniscectomized knees, bone volume/tissue volume (BV/TV) was lower, whereas trabecular separation, the OA score, and aggrecanase expression were higher than in the sham-operated knees. After treatment with OPG, BV/TV was significantly increased and trabecular separation was reduced in the knees that underwent meniscectomy. The OA score and the number of ADAMTS-positive cells were significantly decreased by treatment with OPG but were not affected by IL-1Ra. Moreover, OPG did not directly reduce the release of proteoglycans from cartilage explant cultures.


CONCLUSIONS
In an experimental model of OA, meniscectomy induced bone loss and cartilage degradation at 6 weeks. Systemic administration of OPG prevented bone and cartilage degradation in vivo but had no effect on cartilage in vitro. These data collectively indicate that bone could be a contributor in the early stages of OA pathogenesis. They further suggest that disruption of RANKL/OPG balance might result in the degradation of cartilage subjected to mechanical loading. Specific targeting of the bone cytokine network might help to prevent OA.
Kadri
A
A
INSERM U606, Université Paris 7, Paris, France.
Ea
H K
HK
Bazille
C
C
Hannouche
D
D
Lioté
F
F
Cohen-Solal
M E
ME
D051722:ADAM Proteins / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002357:Cartilage Diseases / Q000378:metabolism / Q000517:prevention & control*; D002358:Cartilage, Articular / Q000378:metabolism*; D004195:Disease Models, Animal; D053590:Interleukin 1 Receptor Antagonist Protein / Q000502:physiology; D008297:Male; D008592:Menisci, Tibial / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology; D053244:Osteoprotegerin / Q000502:physiology*; D011348:Procollagen N-Endopeptidase / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism
C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D053244:Osteoprotegerin; D011509:Proteoglycans; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603919:Adamts4 protein, mouse