The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA͞1 mice with type II collagen (CII) in complete Freund's adjuvant. The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg͞kg per day i.p. or 25 mg͞kg per day orally. Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-␥ production, as well as a decreased release of tumor necrosis factor by knee synovial cells. In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes. It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57͞BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.
Objective/Method Aggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (OA). Results Structural mapping predicts the most potent mAbs employ a unique mode of inhibition by cross-linking the catalytic and disintegrin domains. In a surgical mouse model of OA, both ADAMTS-5 and ADAMTS-4-specific mAbs penetrate cartilage following systemic administration, demonstrating access to the anticipated site of action. Structural disease modification and associated alleviation of pain-related behavior were observed with ADAMTS-5 mAb treatment. Treatment of human OA cartilage demonstrated a preferential role for ADAMTS-5 inhibition over ADAMTS-4, as measured by ARGS neoepitope release in explant cultures. ADAMTS-5 mAb activity was most evident in a subset of patient-derived tissues and suppression of ARGS neoepitope release was sustained for weeks after a single treatment in human explants and in cynomolgus monkeys, consistent with high affinity target engagement and slow ADAMTS-5 turnover. Conclusion This data supports a hypothesis set forth from knockout mouse studies that ADAMTS-5 is the major aggrecanase involved in cartilage degradation and provides a link between a biological pathway and pharmacology which translates to human tissues, non-human primate models and points to a target OA patient population. Therefore, a humanized ADAMTS-5-selective monoclonal antibody (GSK2394002) was progressed as a potential OA disease modifying therapeutic.
Purpose of review Anti-NGF antibodies hold tremendous potential for the management of osteoarthritis (OA) pain, but clinical trials have revealed serious adverse effects that are incompletely understood. This review discusses clinical trial results along with preclinical studies that have assessed NGF blockade in experimental OA, in order to provide insight for future studies. Recent findings Systematic reviews have revealed that anti-NGF therapy, including tanezumab, is efficacious in improving pain and function, but serious adverse events, including rapidly progressive OA and osteonecrosis, resulted in a moratorium on trials that was only recently lifted. Within the past year, preclinical testing has revealed effects of NGF blockade on both pain behaviors and joint structure in experimental models of OA. Similar to clinical trial results, these studies in laboratory animals demonstrated analgesic efficacy of NGF blockade. Interestingly, several animal studies have suggested detrimental effects on joint integrity as a result of treatment, particularly when treatment is started early in the disease, when joint damage is mild to moderate. Summary NGF blockade continues to represent a promising new approach for the treatment of OA pain, but the actual benefits and risks remain to be fully elucidated. Preclinical models may suggest patient populations that could be best served while limiting side effects, but future work should further investigate the mechanisms of benefits and unwanted side effects.
Both peripheral and central mechanisms contribute to OA pain. Clinical evidence suggests that a strong peripheral nociceptive drive from the affected joint maintains pain and central sensitization associated with OA. Mediators present in the OA joint, including nerve growth factor, chemokines, cytokines, and inflammatory cells can contribute to sensitization. Furthermore, structural alterations in joint innervation and nerve damage occur in the course of OA. Several interrelated pathological processes, including joint damage, structural reorganization of joint afferents, low-grade inflammation, neuroplasticity, and nerve damage all contribute to the pain observed in OA. It can be anticipated that elucidating exactly how these mechanisms are operational in the course of progressive OA may lead to the identification of novel targets for intervention.
Objectives: To document the nociceptive innervation of the normal and osteoarthritic murine knee. Methods: Knees were collected from naïve male C57BL/6 Na V 1.8-tdTomato reporter mice aged 10, 26, and 52 weeks (n ¼ 5/group). Destabilization of the medial meniscus (DMM) or sham surgeries (n ¼ 5/ group) were performed in the right knee of 10-week old male Na V 1.8-tdTomato mice, and knees were harvested 16 weeks later. Twenty 20-mm frozen sections from a 400-mm mid-joint region were collected for confocal microscopy. Integrated density of the tdTomato signal was calculated using Image J by two independent observers blinded to the groups. Consecutive sections were stained with hematoxylin & eosin. C57BL/6-Pirt-GCaMP3 mice (n ¼ 5/group) and protein gene product 9.5 (PGP9.5) immunostaining of C57BL/6 wild type (WT) mice (n ¼ 5/group) were used to confirm innervation patterns. Results: In naive 10-week old mice, nociceptive innervation was most dense in bone marrow cavities, lateral synovium and at the insertions of the cruciate ligaments. By age 26 weeks, unoperated knees showed a marked decline in nociceptors in the lateral synovium and cruciate ligament insertions. No further decline was observed by age 1 year. Sixteen weeks after DMM, the medial compartment of OA knees exhibited striking changes in Na V 1.8þ innervation, including increased innervation of the medial synovium and meniscus, and nociceptors in subchondral bone channels. All results were confirmed through quantification, also in Pirt-GCaMP3 and PGP9.5-immunostained WT mice. Conclusions: Nociceptive innervation of the mouse knee markedly declines by age 26 weeks, before onset of spontaneous OA. Late-stage surgically induced OA is associated with striking plasticity of joint afferents in the medial compartment of the knee.
There is a big need for the development of novel therapies for the safe management of chronic pain associated with OA. Here we reviewed PubMed (2015 onward) and ClinicalTrials.gov for ongoing and recently completed trials where pain in OA is the primary outcome measure. Three broad categories were identified: biological therapies, small molecules and cryoneurolysis. The most promising new strategy is blockade of nerve growth factor with antibodies. Two anti-nerve growth factor antibodies, tanuzemab and fasinumab, are in active development after the 2010 hold on trials was lifted in 2015. In addition, several active clinical trials are testing distinct mechanism-based interventions, including cytokine inhibition, selective μ, δ or κ opioid receptor agonists, zoledronate and intra-articular capsaicin. In addition to pharmacological approaches, cryoneurolytic strategies that directly target peripheral nerves may play a role in OA pain management, but efficacy profiles and long-term effects of such treatments need more study. Clearly, the therapeutic landscape for OA pain is rapidly expanding. Since symptomatic OA is a heterogeneous disease, the challenge will be to identify patients that will benefit the most from specific approaches.
All experimental models of osteoarthritis (OA)-like joint damage are accompanied by behaviors indicative of pain. In experimental knee OA, evoked pain responses to exogenously applied stimuli suggest that animals become sensitized to mechanical stimuli. Neurobiological techniques, including electrophysiology and in vivo calcium imaging, confirm that joint damage is associated by peripheral sensitization to mechanical stimuli. Several mediators present in the OA joint can cause peripheral sensitization, most notably the neurotrophin, nerve growth factor. Furthermore, experimental OA is associated with neuro-inflammation in the peripheral and central nervous systems, including macrophage infiltration of the dorsal root ganglia and microglial activation in the spinal cord. Increasingly, researchers are employing models that are slowly progressive, and this approach has revealed that distinct pain mechanisms operate in a time-dependent manner, which may have important translational significance. While the study of pain in experimental OA is rapidly evolving, applying increasingly sophisticated techniques to assess pain and unravel the neurobiology of its genesis, important gaps and limitations in our current approaches exist, which our research community needs to address.
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