Blocking of tumor necrosis factor activity promotes natural repair of osteochondral defects in rabbit knee

Abstract

Background and purpose Osteochondral defects have a limited capacity for repair. We therefore investigated the effects of tumor necrosis factor (TNF) signal blockade by etanercept (human recombinant soluble TNF receptor) on the repair of osteochondral defects in rabbit knees.Material and methods Osteochondral defects (5 mm in diameter) were created in the femoral patellar groove in rabbits. Soon after the procedure, a first subcutaneous injection of etanercept was performed. This single injection or, alternatively, 4 injections in total (twice a week for 2 weeks) were given. Each of these 2 groups was divided further into 3 subgroups: a low-dose group (0.05 μg/kg), an intermediate-dose group (0.4 μ g/kg), and a high-dose group (1.6 μ g /kg) with 19 rabbits in each. As a control, 19 rabbits were injected with water alone. The rabbits in each subgroup were killed 4 weeks (6 rabbits), 8 weeks (6 rabbits), or 24 weeks (7 rabbits) after surgery and repair was assessed histologically.Results Histological examination revealed that the natural process of repair of the osteochondral defects was promoted by 4 subcutaneous injections of intermediate-dose etanercept and by 1 or 4 injections of high-dose etanercept at the various time points examined postoperatively (4, 8, and 24 weeks). Western blot showed that rabbit TNFα had a high affinity for etanercept.Interpretation Blocking of TNF by etanercept enabled repair of osteochondral defects in rabbit knee. Anti-TNF therapy could be a strategy for the use of tissue engineering for bone and cartilage repair.

Anti-Inflammatory Strategies in Cartilage Repair

“…37 An in vivo study showed that subcutaneous injection of etanercept promoted repair of osteochondral defects in the rabbit knee. 38 Application of the anti-TNFa monoclonal antibody in polyarthritic transgenic mice demonstrated reversal of cartilage degradation in the young mice. 39 Besides IL-1b and TNFa, proinflammatory cytokines, such as IL-6, 40 leukemia inhibitory factor, 41 and the chemokine IL-8, 42 may modulate the direct catabolic effects of some cytokines.…”

Targeting anti‐chondrogenic factors for the stimulation of chondrogenesis: A new paradigm in cartilage repair

“…When cartilage is damaged, high levels of extracellular mediators of inflammation including pro‐inflammatory cytokines and chemokines are produced by joint tissues and released in the synovial fluid . While low levels of these factors are required as initial stimulus for tissue repair, their increased or chronic production can impair chondrogenesis and stimulate the degeneration of newly‐formed cartilage . Among pro‐inflammatory mediators, IL‐1β, TNFα, members of the IL‐6 family, and IL‐8 are well recognized as potent anti‐chondrogenic factors .…”

“…Modulation of inflammation via targeted inhibition of pro‐inflammatory signals could offer great therapeutic benefits, by reducing cartilage degeneration and creating a favorable environment for repair. Kawaguchi et al showed that the repair of osteochondral defects in rabbit could be improved by injection of the TNF‐inhibitor etanercept. However, modulation of inflammation represents a considerable challenge since non‐selective inhibition of inflammation via non‐steroidal anti‐inflammatory drugs (NSAIDs) was found to inhibit chondrogenesis and cartilage production .…”

“…these factors are required as initial stimulus for tissue repair, their increased or chronic production can impair chondrogenesis and stimulate the degeneration of newly-formed cartilage. [38][39][40] Among pro-inflammatory mediators, IL-1b, TNFa, members of the IL-6 family, and IL-8 are well recognized as potent antichondrogenic factors. 41 These cytokines induce the transcription factor NF-kB, which can inhibit the expression of SOX9 and TGF-b receptor type II, and block SMADs phosphorylation.…”

Bioresponsive microspheres for on‐demand delivery of anti‐inflammatory cytokines for articular cartilage repair

“…Among the many inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) signaling and interleukin 1 beta (IL-1β) are the major mediators of cartilage destruction (Malemud, 2004). Inhibitors of secretion/activity of TNF-α and IL-1β including receptor agonists and monoclonal antibodies are capable of mitigating cartilage breakdown (Kawaguchi et al, 2009;Martel-Pelletier, Mineau, Jolicoeur, Cloutier, & Pelletier, 1998;Scott & Kingsley, 2006). Inhibitors of secretion/activity of TNF-α and IL-1β including receptor agonists and monoclonal antibodies are capable of mitigating cartilage breakdown (Kawaguchi et al, 2009;Martel-Pelletier, Mineau, Jolicoeur, Cloutier, & Pelletier, 1998;Scott & Kingsley, 2006).…”