Contribution of synovial macrophages to rat advanced osteoarthritis pain resistant to cyclooxygenase inhibitors

Abstract

Most advanced knee osteoarthritis (OA) patients experience chronic pain resistant to cyclooxygenase (COX) inhibitors. However, the cells and molecules involved in this advanced OA pain remain poorly understood. In this study, we developed a rat model of advanced knee OA by modification of the monoiodoacetate-induced OA pain model and examined involvement of synovial macrophages in advanced OA pain. Cyclooxygenase inhibitors, such as celecoxib and naproxen, and a steroid were ineffective, but an opioid and anti–nerve growth factor (NGF) antibody was effective for pain management in the advanced OA model. Similar to advanced OA patients, histological analysis indicated severe bone marrow damages, synovitis, and cartilage damage and an increase of macrophages with high expression of interleukin-1β, NGF, nitric oxide synthase (NOS) 1, NOS2, and COX-2 in the knee joint of the advanced OA model. Intravenous injection of clodronate liposomes depleted synovial macrophages, which decreased the level of not only proinflammatory mediator interleukin-1β but also NGF in the knee joint, leading to pain suppression in the advanced OA model. These data suggest the involvement of synovial macrophages in advanced knee OA pain resistant to COX inhibitors by increasing proinflammatory mediators, and that drugs targeting synovial macrophages might have potent analgesic effects.

Therapeutic Manipulation of Macrophages Using Nanotechnological Approaches for the Treatment of Osteoarthritis

“…Interestingly, an increase in the nerve growth factor, related with persistent pain in OA patients, was also observed [78]. Similar findings were also reported in rat models of monoiodoacetate-induced OA [123]. In contrary to these results, a very recent study by Bailey et al has demonstrated that intra-articular injection of clodronate liposomes in post-traumatic arthritis murine models did not reduce the synovitis, and the M1/M2 ratio was increased in some treated mice, advocating that clodronate liposomes could lead to the depletion not only of the M1 pro-inflammatory macrophages, but also of the M2-like immunomodulator counterparts [124].…”

Identification of key biomarkers and immune infiltration in the synovial tissue of osteoarthritis by bioinformatics analysis

“…However, its gene expression in OA was downregulated compared with that in normal controls in our study. Many advanced OA patients experience chronic pain resistant to cyclooxygenase (COX) inhibitors (Sakurai et al, 2019). Another study also showed a lack of the chondroprotective effect of cyclooxygenase 2 inhibition in a surgically-induced model of osteoarthritis in mice.…”

Emerging Evidence of Macrophage Contribution to Hyperinnervation and Nociceptor Sensitization in Vulvodynia

“…Macrophages are implicated in the regulation of pain sensitivity in multiple conditions (Gong et al, 2016; Shepherd et al, 2018; Sakurai et al, 2019). Macrophage infiltration has been demonstrated in pain-associated synovial tissue from patients with advanced osteoarthritis and in pain-associated models of joint, muscle and paw inflammation (Gong et al, 2016; Shepherd et al, 2018; Sakurai et al, 2019). More importantly, macrophage depletion via clodronate liposomes reduces the elevated pro-inflammatory cytokines and NGF and reduces pain behaviors in a model of arthritis (Sakurai et al, 2019).…”

“…Macrophage infiltration has been demonstrated in pain-associated synovial tissue from patients with advanced osteoarthritis and in pain-associated models of joint, muscle and paw inflammation (Gong et al, 2016; Shepherd et al, 2018; Sakurai et al, 2019). More importantly, macrophage depletion via clodronate liposomes reduces the elevated pro-inflammatory cytokines and NGF and reduces pain behaviors in a model of arthritis (Sakurai et al, 2019). Similarly, macrophage depletion prevents local hyperalgesia in response to plantar injection of angiotensin II (Shepherd et al, 2018), and widespread hyperalgesia in response to repeated intra-muscular injection of acidic saline and pro-inflammatory agents (Gong et al, 2016).…”

“…The ability of macrophages to induce nerve sprouting is shown in sympathetic hyperinnervation following myocardial infarction in a mechanism involving their production of NGF (Hasan et al, 2006; Wernli et al, 2009). NGF also contributes to sensory hyperinnervation and hyperalgesia in response to inflammation (Woolf et al, 1994), and anti-NGF therapy has anti-nociceptive effects in the treatment of arthritis (Sakurai et al, 2019). Macrophages are an important source of NGF following injury (Lindholm et al, 1987).…”