Antibody-induced pain-like behavior and bone erosion: links to subclinical inflammation, osteoclast activity, and acid-sensing ion channel 3–dependent sensitization

Abstract

Several bone conditions, eg, bone cancer, osteoporosis, and rheumatoid arthritis (RA), are associated with a risk of developing persistent pain. Increased osteoclast activity is often the hallmark of these bony pathologies and not only leads to bone remodeling but is also a source of pronociceptive factors that sensitize the bone-innervating nociceptors. Although historically bone loss in RA has been believed to be a consequence of inflammation, both bone erosion and pain can occur years before the symptom onset. Here, we have addressed the disconnection between inflammation, pain, and bone erosion by using a combination of 2 monoclonal antibodies isolated from B cells of patients with RA. We have found that mice injected with B02/B09 monoclonal antibodies (mAbs) developed a long-lasting mechanical hypersensitivity that was accompanied by bone erosion in the absence of joint edema or synovitis. Intriguingly, we have noted a lack of analgesic effect of naproxen and a moderate elevation of few inflammatory factors in the ankle joints suggesting that B02/B09-induced pain-like behavior does not depend on inflammatory processes. By contrast, we found that inhibiting osteoclast activity and acid-sensing ion channel 3 signaling prevented the development of B02/B09-mediated mechanical hypersensitivity. Moreover, we have identified secretory phospholipase A2 and lysophosphatidylcholine 16:0 as critical components of B02/B09-induced pain-like behavior and shown that treatment with a secretory phospholipase A2 inhibitor reversed B02/B09-induced mechanical hypersensitivity and bone erosion. Taken together, our study suggests a potential link between bone erosion and pain in a state of subclinical inflammation and offers a step forward in understanding the mechanisms of bone pain in diseases such as RA.

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

“…From numerous reports, it has been clarified that the level and metabolism process of LPC in the body fluid or tissues of animals or humans are elevated in various chronic pain states, such as chronic inflammatory pain [ 81 ], chronic joint pain [ 82 , 83 ] neuropathic pain [ 29 , 39 , 84 ], fibromyalgia [ 16 ], and multisite musculoskeletal pain [ 38 ] ( Table 2 ). In this section, we summarize these LPC-induced responses and cellular mechanisms in detail.…”

“…Chronic joint pain is the main reason for patients to seek medical treatment for chronic pain; it seriously affects the quality of life of patients, resulting in disability and psychological distress [ 82 ]. Rheumatoid arthritis (RA) and osteoarthritis (OA) are associated with a risk of developing persistent chronic joint pain [ 83 ]. Florian Jacquot et al demonstrated that LPC correlated with pain outcomes in a cohort of chronic joint pain patients.…”

“…In addition, elevated levels of LPC and sPLA2, a family of enzymes required for LPC synthesis, have been verified in the plasma and synovial fluid of patients with RA and OA, as well as those with joint pain. Consequently, it was possible that LPC was regarded as a biological target for predicting chronic joint pain in rodents or humans, especially LPC (16:0) ( Figure 3 ) [ 83 ].…”

“…Of course, not all LPC will eventually be converted into LPA. The indications of the increased expression of the LPC to LPA-converting enzyme autotaxin or LPA receptors were not found in several chronic pain models [ 83 ]. This is because pathological pain is a complex state that may be related to both the model and the time of onset.…”

Fibromyalgia patients with high levels of anti-satellite glia cell IgG antibodies present with more severe symptoms

“…To identify potential drivers of nociplastic pain in FM we used a passive transfer mouse model to investigate a role for pathogenic, pain-driving IgG antibodies (9). IgG can induce pain independent of overt inflammation or nerve damage (10–12) and a role for antibodies has been identified in other nociplastic pain conditions (13–15). We found that transferring FM IgG into mice induces pain-like behaviour, nociceptor sensitization and hyperactivity, and decreased intraepidermal nerve fiber density (9), all of which are characteristics of FM (4,5).…”