Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing

Flick, Lisa M.; Weaver, Jason M.; Ulrich-Vinther, Michael; Abuzzahab, F. S.; Zhang, Xinping; Dougall, William C.; Anderson, D. C.; O’Keefe, Regis J.; Schwarz, Edward M.

doi:10.1016/s0736-0266(03)00011-1

Cited by 73 publications

(55 citation statements)

References 32 publications

(21 reference statements)

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“…12 Nuclear factor-kappa B ligand inhibition in animal fracture models has established the importance of osteoclasts/chondroclasts in cartilaginous-to-boney callus transition. [55][56][57] Profound inhibition of osteoclast formation was confirmed in most models. Interestingly, the remaining callus consisted of mineralized and vascularized cartilage 55 that was mechanically sound.…”

Section: Macrophage Participation In Hard Callus Formation and Remodementioning

confidence: 75%

Unraveling macrophage contributions to bone repair

et al. 2013

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Macrophages have reemerged to prominence with widened understanding of their pleiotropic contributions to many biologies and pathologies. This includes clear advances in revealing their importance in wound healing. Here we have focused on the current state of knowledge with respect to bone repair, which has received relatively little scientific attention compared with its soft-tissue counterparts. Our detailed characterization of resident tissue macrophages residing in bone-lining tissues (osteomacs), including their pro-anabolic function, exposed a more prominent role for these cells in bone biology than previously anticipated. Recent studies have confirmed the importance of macrophages in early inflammatory processes that establish the healing cascade after bone fracture. Emerging data support that macrophage influence extends into both anabolic and catabolic phases of repair, suggesting that these cells have prolonged and diverse functions during fracture healing. More research is needed to clarify macrophage phase-specific contributions, temporospatial subpopulation variance and macrophage specific-molecular mediators. There is also clear motivation for determining whether macrophage alterations underlie compromised fracture healing. Overall, there is strong justification to pursue strategies targeting macrophages and/or their products for improving normal bone healing and overcoming failed repair.

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Section: Macrophage Participation In Hard Callus Formation and Remodementioning

confidence: 75%

Unraveling macrophage contributions to bone repair

et al. 2013

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“…The absence of IL-6 during this period could conceivably impair remodeling. In a study of antibodymediated abrogation of RANK signaling, Flick et al 40 noted that fractures in mice treated acutely healed unremarkably while chronic antibody administration produced osteopetrotic bone. As well, RANK knockouts produced a similar outcome.…”

Section: Discussionmentioning

confidence: 99%

Effects of Interleukin‐6 Ablation on Fracture Healing in Mice

Wallace

Cooney

Englund

et al. 2011

Journal Orthopaedic Research

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This study examined the impact of an interleukin-6 (IL-6) knockout on fracture healing in terms of histological and biomechanical responses. Following IACUC approval, tibial fractures were produced in 4-to 6-week-old IL-6 knockouts (n ¼ 35) and wild-type mice (n ¼ 36) and harvested along with contralateral limbs at 2 and 6 weeks postsurgery. Histology quantified stage of healing, lymphocyte infiltration, TRAPþ cells, and osteocalcin deposition. Bend testing established maximum load and stiffness. Based on normality assessments, Mann-Whitney U or independent t-tests were used for data analysis using a p-value threshold of 0.05. Stage of healing, lymphocyte infiltration, and osteocalcin deposition were similar for all time points (p ! 0.243). TRAPþ cell counts were reduced approximately 10-fold in the knockout at 2 weeks (p ¼ 0.015) but were similar at 6 weeks (p ¼ 0.689). Force-to-failure in knockouts was approximately 40% that of wild-type mice at 2 weeks (p ¼ 0.040) but similar at 6 weeks (p ¼ 0.735). Knockout bone was about 25% less stiff at 2 weeks but approximately 60% stiffer at 6 weeks (p ! 0.110). The absence of IL-6 during early fracture healing significantly reduced osteoclastogenesis and impaired callus strength. By 6 weeks, most histological and biomechanical parameters were similar to fractures in wild-type bone. Keywords: cytokines; interleukin-6; fracture healing Inflammation is a key component to both wound and bony healing responses. Leukocytosis is a part of this phenomenom and is integral to fracture healing.1-3 In particular, neutrophil infiltration is apparently allied with establishing chondrogenesis, a sentinel component of endochondral ossification. 4Cytokines are also involved in regulating the healing response. IL-1 plays a prominent role in the early response to injury, 5-7 exerting both proliferative [7][8][9][10] and catabolic effects. 11 It also stimulates the expression of IL-6 by osteoblasts. [12][13][14] There is a substantial body of research that suggest that IL-6 exerts effects on bone homeostasis and repair. IL-6 stimulates production of RANK ligand by osteoblasts which, in turn, catalyzes the formation of osteoclasts from peripheral blood monocytes.15 It was shown to induce differentiation of pre-osteoblasts, [16][17][18] inhibit nodule formation in bone culture, 19 and induce cathepsin B production by osteoblasts.20 During distraction osteogenesis, IL-6 is produced by osteoblasts, hemopoietic cells, and cells associated with the lengthening callus. 21 Murine models of fracture healing have shown elevations in IL-6 during intramembranous callus remodeling 22 as well as secondary bone remodeling associated with endochondral ossification. 23 Recently, Yang et al. 24 provided insight into the effects of IL-6 on fracture healing, noting an impairment of osteoclastogenesis. Similarly, Axmann et al. 25 showed that abrogating IL-6 receptor function also reduced osteoclast counts in a model of inflammatory (RA) bone erosion.Given the importance of the inflammatory response ...

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“…In mice, severe osteoclast depletion with high dose RANK-Fc treatment has no significant effect on fracture healing [Flick et al 2003]. In a recent study of male RANKL knock-in mice that expressed a chimeric (human/murine) form of RANKL, denosumab delayed the removal of cartilage and the remodeling of fracture callus but did not diminish the mechanical integrity of the healing fractures [Gerstenfeld et al 2009].…”

Section: Fracture Healingmentioning

confidence: 99%

Denosumab in postmenopausal osteoporosis: what the clinician needs to know

Lewiecki

2009

Therapeutic Advances in Musculoskeletal

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Denosumab is a subcutaneously (SC) administered investigational fully human monoclonal antibody to receptor activator of nuclear factor-kB ligand (RANKL), a cytokine member of the tumor necrosis factor family that is the principal mediator of osteoclastic bone resorption. RANKL stimulates the formation, activity, and survival of osteoclasts, and is implicated in the pathogenesis of postmenopausal osteoporosis and other skeletal disorders associated with increased bone remodeling. Denosumab binds RANKL, preventing it from binding to RANK, thereby reducing the formation, activity, and survival of osteoclasts and slowing the rate of bone resorption. Postmenopausal women with low bone mineral density (BMD) treated with denosumab have a reduction of bone turnover markers and an increase in BMD that is rapid, sustained, and reversible. In postmenopausal women with osteoporosis, denosumab reduces the risk of vertebral, hip, and nonvertebral fractures. In postmenopausal women with low BMD randomized to receive denosumab or alendronate, denosumab is associated with a significantly greater increase in BMD and further reduction in bone turnover markers compared with alendronate. In postmenopausal women with low BMD who were previously treated with alendronate, those who switched to denosumab have a significantly greater BMD increase and further reduction in bone turnover markers compared with those continuing alendronate. Denosumab is well tolerated with a favorable safety profile. It is a promising emerging drug for the prevention and treatment of osteoporosis, offering a long dosing interval of every 6 months and convenient SC dosing, with the potential of improving long-term adherence to therapy compared with current oral treatments.

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Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing

Cited by 73 publications

References 32 publications

Unraveling macrophage contributions to bone repair

Unraveling macrophage contributions to bone repair

Effects of Interleukin‐6 Ablation on Fracture Healing in Mice

Denosumab in postmenopausal osteoporosis: what the clinician needs to know

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