Session Type: Abstract Submissions (ACR)
Background/Purpose Osteoclasts play a critical role in homeostatic bone turnover and pathologic bone destruction. Netrin-1, expressed in the marrow only by osteoclast precursors, acts in an autocrine manner via its receptor Unc5b (but not its receptor DCC) to stimulate osteoclast differentiation in vitro. Here we tested the hypothesis that blockade of Netrin-1 or Unc5b diminishes wear particle-induced osteolysis in a mouse model
Methods A 1-cm midline sagittal incision was made over the anterior calvarium to the line connecting both ears in anesthetized 6-8-wk-old male C57BL/6 mice. 3mg of dried UHMWPE particles were implanted and animals were treated with either 0.9% saline, Netrin-1 antibody, Unc5b antibody or DCC antibody (Rabbit polyclonal for all). 100µg antibodies were injected intraperitonally the day of surgery and then once a week. Animals were sacrificed after 14 days and calvaria were removed, fixed, and prepared for microCT and histology. Netrin-1 immunostaining was performed in human tissue obtained following primary prosthesis implantation or after prosthesis revision for peri-implant osteolysis and aseptic implant loosening.
Weekly ip injection of anti-Netrin-1 or anti-Unc5b antibodies significantly reduced the area of particle-induced bone pitting in calvaria exposed to UHMWPE (46±4 and 49±3% bone pitting, respectively, compared to control, p<0.001, n=5) but anti-DCC receptor antibody did not affect UHMWPE-induced pitting and resorption (80±7% bone pitting, p=ns vs control). MicroCT also revealed a significant increase in bone volume (BV) and bone volume/total volume ratio (BV/TV) in both Netrin-1 and Unc5b antibody treated mice. Anti-Netrin-1 or anti-unc5b antibody treatment markedly reduced both the inflammatory infiltrate and the number of TRAP-positive osteoclasts in affected bone (7±1 and 4±1 cells/hpf respectively vs. 12±1 for control, p<0.001). In contrast, treatment with anti-DCC antibody did not significantly reduce the number of osteoclasts in affected bone. There were no significant changes in Alkaline Phosphatase positive osteoblasts on bone forming surfaces in any antibody-treated group compared to control (8±1, 10±1 and 10±2 cells/hpf, vs. 10±1 for control, p=ns). The peri-implant tissues of patients undergoing prosthesis revision surgery show a similar increase in Netrin-1 expression whereas there is little Netrin-1 expression by cells in soft tissues removed at the time of primary joint replacement.
Conclusion These results demonstrate a unique role for netrin-1 in osteoclast biology; netrin-1 is an autocrine and paracrine regulator of osteoclast differentiation and may be a novel target for prevention or treatment of inflammatory osteolysis.
S. R. Goldring,
B. N. Cronstein,
NYU School of Medicine,
Eli Lilly and Company,
Rheumatology Reseach Foundation,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/netrin1-is-highly-expressed-and-required-in-inflammatory-infiltrates-in-wear-particle-induced-osteolysis/