The anti-NGF antibody muMab 911 both prevents and reverses pain behaviour and subchondral osteoclast numbers in a rat model of osteoarthritis pain

Xu, Luting; Nwosu, Lilian Ngozi; Burston, James J.; Millns, Paul; Sagar, Devi Rani; Mapp, P.I.; Meesawatsom, Pongsatorn; Li, L.; Bennett, Andrew J.; Walsh, David A.; Chapman, Victoria

doi:10.1016/j.joca.2016.05.015

Cited by 49 publications

(45 citation statements)

References 41 publications

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“…The use of osteoprotegerin reduced the development of pain behavior and joint pathology in the MIA model (Sagar et al, 2014 ). As mentioned above, the anti-NGF antibody muMab911 prevented and reversed pain behavior and subchondral osteoclast numbers in the MIA model but did not alter cartilage and synovial pathology (Xu et al, 2016 ).…”

Section: Considerations On Present and Future Therapeutical Possibilimentioning

confidence: 90%

“…Similarly, another study found in the MIA model a late increase of NGF (in conjunction with a neuropathic component), whereas in the first phase, TNF and IL-6 were elevated (Orita et al, 2011a ). The anti-NGF antibody muMab911 prevented and reversed pain behavior and subchondral osteoclast numbers in the MIA model but did not alter cartilage and synovial pathology (Xu et al, 2016 ).…”

Section: Mediators Involved In Oa Painmentioning

confidence: 99%

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Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models

Eitner

Hofmann

Schaible

2017

Front. Mol. Neurosci.

175

156

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Pain due to osteoarthritis (OA) is one of the most frequent causes of chronic pain. However, the mechanisms of OA pain are poorly understood. This review addresses the mechanisms which are thought to be involved in OA pain, derived from studies on pain mechanisms in humans and in experimental models of OA. Three areas will be considered, namely local processes in the joint associated with OA pain, neuronal mechanisms involved in OA pain, and general factors which influence OA pain. Except the cartilage all structures of the joints are innervated by nociceptors. Although the hallmark of OA is the degradation of the cartilage, OA joints show multiple structural alterations of cartilage, bone and synovial tissue. In particular synovitis and bone marrow lesions have been proposed to determine OA pain whereas the contribution of the other pathologies to pain generation has been studied less. Concerning the peripheral neuronal mechanisms of OA pain, peripheral nociceptive sensitization was shown, and neuropathic mechanisms may be involved at some stages. Structural changes of joint innervation such as local loss and/or sprouting of nerve fibers were shown. In addition, central sensitization, reduction of descending inhibition, descending excitation and cortical atrophies were observed in OA. The combination of different neuronal mechanisms may define the particular pain phenotype in an OA patient. Among mediators involved in OA pain, nerve growth factor (NGF) is in the focus because antibodies against NGF significantly reduce OA pain. Several studies show that neutralization of interleukin-1β and TNF may reduce OA pain. Many patients with OA exhibit comorbidities such as obesity, low grade systemic inflammation and diabetes mellitus. These comorbidities can significantly influence the course of OA, and pain research just began to study the significance of such factors in pain generation. In addition, psychologic and socioeconomic factors may aggravate OA pain, and in some cases genetic factors influencing OA pain were found. Considering the local factors in the joint, the neuronal processes and the comorbidities, a better definition of OA pain phenotypes may become possible. Studies are under way in order to improve OA and OA pain monitoring.

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Section: Considerations On Present and Future Therapeutical Possibilimentioning

confidence: 90%

Section: Mediators Involved In Oa Painmentioning

confidence: 99%

Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models

Eitner

Hofmann

Schaible

2017

Front. Mol. Neurosci.

175

156

View full text Add to dashboard Cite

show abstract

“…NGF and TrkA are expressed by osteoclasts, and the addition of NGF to monocyte cultures induces the formation of TRAP‐positive multinucleated cells . An anti‐NGF antibody reduced subchondral osteoclast numbers in a rat model of OA pain .…”

Section: Discussionmentioning

confidence: 99%

Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone

Aso

Shahtaheri

Hill

et al. 2019

Arthritis & Rheumatology

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Objective. Subchondral bone and the osteochondral junction are thought to contribute to osteoarthritis (OA) knee pain. We undertook this study to identify osteochondral pathologies specifically associated with symptomatic human knee OA.Methods. Medial tibial plateau samples from 2 groups of subjects (n = 31 per group) were matched for macroscopic chondropathy scores. The symptomatic chondropathy group had undergone total knee replacement for OA knee pain, at which time specimens of the medial tibial plateau were obtained. The asymptomatic chondropathy group included subjects who died of unrelated illness (specimens were obtained at postmortem examination) and who had not previously sought help for knee pain. OA histopathology, immunoreactivity for nerve growth factor (NGF) and CD68 (macrophages), tartrate-resistant acid phosphatase-positive subchondral osteoclasts, and synovitis were compared between groups.Results. Mankin scores, subchondral bone density, and subchondral CD68-immunoreactive macrophage infiltration were similar between the 2 groups. NGF-like immunoreactivity was found in subchondral mononuclear cells and osteoclasts, as well as in chondrocytes. NGF in osteochondral channels and osteoclast densities in subchondral bone were higher in the symptomatic chondropathy group than in the asymptomatic chondropathy group (P < 0.01 and P = 0.02, respectively), as were synovitis scores (P < 0.01). Osteochondral pathology was not significantly associated with synovitis score. The differences in NGF expression and in osteoclast density remained significant after adjustment for age and synovitis score (P = 0.01 and P = 0.04, respectively). Osteochondral NGF and osteoclast densities, together with synovitis scores, explained ~28% of sample allocation to symptomatic or asymptomatic groups.Conclusion. Subchondral pathology was associated with symptomatic knee OA, independent of chondropathy and synovitis. Increased NGF expression in osteochondral channels and increased osteoclast density appear to be key features associated with bone pain in knee OA.

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“…Under inflammatory conditions, NGF expression is up-regulated by cytokines, and inflammatory cells such as mast cells release NGF 2 . Indeed, extracellular NGF levels are higher in inflamed joints and NGF blockade with both TrkA-IgG fusion protein and NGF monoclonal antibodies produces analgesic effects in preclinical settings 3,4 . Relevantly, humanised monoclonal anti-NGF antibodies are effective analgesics in people with osteoarthritis joint pain 5 .…”

Section: Introductionmentioning

confidence: 99%