Effects of knockout of the receptor for advanced glycation end‐products on bone mineral density and synovitis in mice with intra‐articular fractures

Abstract

Our group employed the mouse closed intra-articular fracture (IAF) model to test the hypothesis that the innate immune system plays a role in initiating synovitis and post-traumatic osteoarthritis (PTOA) in fractured joints. A transgenic strategy featuring knockout of the receptor for advanced glycation end-products (RAGE ) was pursued. The 42 and 84 mJ impacts used to create fractures were in the range previously reported to cause PTOA at 60 days post-fracture. MicroCT (μCT) was used to assess fracture patterns and epiphyseal and metaphyseal bone loss at 30 and 60 days post-fracture. Cartilage degeneration, synovitis, and matrix metalloproteinase (MMP-3, -13) expression were evaluated by histologic analyses. In wild-type mice, μCT imaging showed that 84 mJ impacts led to significant bone loss at 30 days (p< 0.05), but recovered to normal at 60 days. Bone losses did not occur in RAGE mice. Synovitis was significantly elevated in 84 mJ impact wild-type mice at both endpoints (30 day, p = 0.001; 60 day, p = 0.05), whereas in RAGE mice synovitis was elevated only at 30 days (p = 0.02). Mankin scores were slightly elevated in both mouse strains at 30 days, but not at 60 days. Immunohistochemistry revealed significant fracture-related increases in MMP-3 and -13 expression at 30 days (p < 0.05), with no significant difference between genotypes. These findings indicated that while RAGE accelerated recovery from fracture and diminished synovitis, arthritic changes were temporary and too modest to detect an effect on the pathogenesis of PTOA. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2439-2449, 2018.

Posttraumatic osteoarthritis: from basic science to clinical implications

“…[14] Increases in IL-1b after IAF were also demonstrated by other investigators using a closed IAF model in mice. [16] These early proinflammatory cytokines are also seen in humans after articular fractures. [10] Subsequent proof-of-concept work using intra-articular administration of IL-1 receptor antagonist (IL-1Ra) after acute IAF in B6 mice showed a significant reduction in histological evidence of PTOA.…”

“…[ 14 ] Increases in IL-1β after IAF were also demonstrated by other investigators using a closed IAF model in mice. [ 16 ] These early proinflammatory cytokines are also seen in humans after articular fractures. [ 10 ]…”

Crosstalk Between Senescent Bone Cells and the Bone Tissue Microenvironment Influences Bone Fragility During Chronological Age and in Diabetes

“…Interestingly, serum IL-6 and pyridinoline (a bone degradation marker) were both decreased in rage – / – mice, suggesting a decreased inflammation profile associated with decreased osteoclast activity ( Ding et al, 2006 ; Zhou et al, 2006 ). Knock-out of RAGE in mice also improved recovery from induced bone fracture, with faster recovery of bone mineral density, trabecular bone volume and thickness, and decreased synovitis ( Seol et al, 2018 ). Whether RAGE impacts on bone fragility in diabetes is more moot, since in young mice with streptozotocin-induced diabetes, RAGE knock-out did not protect against bone loss, as measured by histomorphometric analyses ( Hamada et al, 2010 ).…”

Osteoarthritis and type 2 diabetes: From pathogenetic factors to therapeutic intervention

“…The activation of the AGE‐RAGE axis seems to be involved in the VEGF‐mediated synovial neoangiogenesis as well, as the administration of AGEs in vitro induced a dose‐dependent expression of VEGF, IL‐6, COX‐2, PGE 2 , and MMP‐13 via the NF‐κB in human synoviocytes . Indeed, an animal study involving a mouse model of intraarticular fracture and subsequent post‐traumatic OA showed a marked grade of synovitis and cartilage degradation due to RAGE activation, while knockout animals for the RAGE gene demonstrated a faster recovery from synovial inflammation and bone fracture, thus not leading to a frank OA …”

“…The activation of the AGE-RAGE axis seems to be involved in the VEGF-mediated synovial neoangiogenesis as well, as the administration of AGEs in vitro induced a dose-dependent expression of VEGF, IL-6, COX-2, PGE 2 , and MMP-13 via the NF-κB in human synoviocytes 66. Indeed, an animal study involving a mouse model of intraarticular fracture and subsequent post-traumatic OA showed a marked grade of synovitis and cartilage degradation due to RAGE activation, while knockout animals for the RAGE gene demonstrated a faster recovery from synovial inflammation and bone fracture, thus not leading to a frank OA 67. Furthermore, AGEs can contribute to induce and/or accelerate OA through the development of diabetic peripheral neuropathy, which presents with paraesthesia, loss of sensation (including nociceptive stimuli), and proprioception, typically involving the distal parts of the limbs.…”