Spinal microglial activation in a murine surgical model of knee osteoarthritis

Tran, Phuong B.; Miller, Rachel E.; Ishihara, Shingo; Miller, Richard J.; Malfait, Anne‐Marie

doi:10.1016/j.joca.2016.09.007

Cited by 39 publications

(33 citation statements)

References 60 publications

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“…Whether a similar sensitization of MSICs and anti-allodynic property of GsMTx4 is present in a slow-progressing or a genetic model of OA pain remains to be elucidated. Furthermore, it is accepted that several central changes occur in the dorsal horn after the aberrant activation of nociceptors that contribute to the maintenance of the mechanical allodynia, including microglial cell proliferation and activation 19,30,48 , as well as increased excitability of wide dynamic range neurons 11 . Our results indicate, however, that a significant portion of the mechanical allodynia is originated from the mechanical activation of MSICs in nociceptors, indicating that these channels represent potentially valuable targets in the treatment of OA pain.…”

Section: Discussionmentioning

confidence: 99%

Mechanosensitive ion channels in articular nociceptors drive mechanical allodynia in osteoarthritis

He¹,

Christin²,

Mouchbahani-Constance

et al. 2017

Osteoarthritis and Cartilage

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Section: Discussionmentioning

confidence: 99%

Mechanosensitive ion channels in articular nociceptors drive mechanical allodynia in osteoarthritis

He¹,

Christin²,

Mouchbahani-Constance

et al. 2017

Osteoarthritis and Cartilage

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“…Besides the induction of spinal hyperexcitability by input from the OA joint, the labeling with markers of neuropathic pain in the DRGs (e.g., ATF3) raise the possibility, that neuropathic mechanisms may contribute as well. Indeed, in both the MIA model (Orita et al, 2011a ; Sagar et al, 2011 ) and the DMM model (Tran et al, 2017 ) the microglia is activated, in the MIA model within a few days, in the DMM models after about 8 weeks, thus reflecting the time course of OA and pain development. However, although microglia activation is a prominent feature of neuropathic pain, it does not per se prove the presence of a neuropathic process because it occurs in inflammatory as well as in neuropathic conditions (Clark et al, 2007 ).…”

Section: Features Of Oa Pain and Neuronal Mechanisms Of Oa Painmentioning

confidence: 99%

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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“…However, we found no evidence for activation of microglia or astrocytes in the ipsilateral dorsal horn of the spinal cord following traditional or modified DMM surgery at 16 weeks post-surgery, compared to sham controls. Previously, microglia activation was reported bilaterally in the dorsal horn of the spinal cord at 8 weeks post DMM surgery [37], which may suggest that our later time point missed the activation of microglia which is known to be transient in models of both OA and neuropathic pain [20,38]. Spinal astrocyte activation often follows microglial activation in OA and neuropathic pain states [20,38].…”

Section: Plos Onementioning

confidence: 69%

Refining surgical models of osteoarthritis in mice and rats alters pain phenotype but not joint pathology

et al. 2020

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The relationship between osteoarthritis (OA) structural change and pain is complex. Surgical models of OA in rodents are often rapid in onset, limiting mechanistic utility and translational validity. We aimed to investigate the effect of refining surgical small rodent models of OA on both joint pathology and pain behaviour. Adult male C57BL/6 mice (n = 76, 10-11 weeks of age at time of surgery) underwent either traditional (transection of the medial meniscotibial ligament [MMTL]) or modified (MMTL left intact, transection of the coronary ligaments) DMM surgery, or sham surgery. Adult male Sprague Dawley rats (n = 76, weight 175-199g) underwent either modified meniscal transection (MMNX) surgery (transection of the medial meniscus whilst the medial collateral ligament is left intact) or sham surgery. Pain behaviours (weight bearing asymmetry [in mice and rats] and paw withdrawal thresholds [in rats]) were measured pre-surgery and weekly up to 16 weeks post-surgery. Post-mortem knee joints were scored for cartilage damage, synovitis, and osteophyte size. There was a significant increase in weight bearing asymmetry from 13 weeks following traditional, but not modified, DMM surgery when compared to sham operated mice. Both traditional and modified DMM surgery led to similar joint pathology. There was significant pain behaviour from 6 weeks following MMNX model compared to sham operated control rats. Synovitis was significant 4 weeks after MMNX surgery, whereas significant chondropathy was first evident 8 weeks post-surgery, compared to sham controls. Pain behaviour is not always present despite significant changes in medial tibial plateau cartilage damage and synovitis, reflecting the heterogeneity seen in human OA. The development of a slowly progressing surgical model of OA pain in the rat suggests that synovitis precedes pain behaviour and that chondropathy is evident later, providing the foundations for future mechanistic studies into the disease.

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Spinal microglial activation in a murine surgical model of knee osteoarthritis

Cited by 39 publications

References 60 publications

Mechanosensitive ion channels in articular nociceptors drive mechanical allodynia in osteoarthritis

Mechanosensitive ion channels in articular nociceptors drive mechanical allodynia in osteoarthritis

Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models

Refining surgical models of osteoarthritis in mice and rats alters pain phenotype but not joint pathology

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