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Levels of LPC16:0 are increased in synovial fluids of patients suffering from joint pain.

Barriere, Kim Kultima, Eva Freyhult, Anders Hugo, Eva Kosek, Aisha S.

Ahmed, Alexandra Jurczak, View ORCID Profile Eric Lingueglia, Camilla I.

Svensson, Vronique Breuil, Thierry Ferreira, View ORCID Profile Fabien Marchand, View ORCID Profile Emmanuel Deval.

Here, we describe increased content of lysophosphatidyl-choline (LPC) 16:0 in the knee synovial fluids of two independent cohorts of patients with painful joint diseases.

If LPC16:0 levels correlated with pain in patients with osteoarthritis (OA), they do not appear to be the hallmark of a particular joint disease.

LPC16:0-induced persistent pain state is dependent on peripheral Acid-Sensing Ion Channel 3 (ASIC3), ultimately leading to central sensitization.

LPC16:0 and ASIC3 thus appear as key players of chronic joint pain with potential implications in OA and possibly across others rheumatic diseases.

Introduction Chronic joint pain is the primary reason why patients seek care from rheumatologists, representing a heavy burden for modern societies 1, 2.

In addition to economical costs, chronic joint pain considerably impairs the patients quality of life, leading to disabilities and psychological distress 1, 3.

Despite major advances in inflammatory arthritis therapies, most patients, especially those suffering from osteoarthritis (OA), continue to experience life-disabling pain.

The development of new therapeutic strategies requires a better understanding of the pathophysiology of joint pain, with careful identification of the triggering factors and associated mechanisms.

In the last two decades, signaling lipids have been shown to contribute to the onset and maintenance of pain.

Lysophosphatidyl-choline (LPC) and lysophosphatidic acid (LPA), the most prominent lyso-glycero-phospholipids 4, are emerging as potential direct pain mediators, besides well-known thromboxanes, leukotrienes and prostaglandins 5, 6.

LPA has been already identified as a key promoter of nerve demyelination and certainly of neuropathic pain 7, 8.

Paradoxically, LPA receptor signaling has also documented physiological roles in myelinating cells during nervous system development 9 11.

The role of LPC in pain remains more elusive, especially in vivo, since its effects could be partially mediated by LPA through the action of autotaxin, the LPC-to-LPA conversion enzyme 12, 13.

Nevertheless, some studies support a direct role of LPC in pain associated to its ability to activatepotentiate pain-related ion channels 5, 6, 14 16.

Moreover, LPC could be particularly important in pain originating from deep tissues such as joints 6, 17 and muscles 18.

Concerning joints, we already reported high levels of LPC in human synovial fluids from patients with painful joint diseases 6 and more recently, an over activation of the conversion pathway of PC-to-LPC has been observed in patients with OA 17.

LPC is able to activate and potentiate pain-related Acid-Sensing Ion Channels 3 (ASIC3) 6, a sub-type of the ASIC channel family, widely expressed in nociceptors and also gated by extracellular protons 19.

ASIC3 have been involved in animal models of inflammatory and non-inflammatory pain 20, 21, especially in the development of chronic pain states originating from joints 22 24 and muscles 18, 25, 26.

Accordingly, ASIC3-dependent pain behaviors can be induced in rodent upon injection of LPC in the paw or the muscle 6, 18.

Here we investigated the clinical relevance of LPC in chronic joint pain and we explored its mechanism of action that involved peripheral ASIC3 channels, using a new preclinical pain model in mice induced by intra-articular administrations of LPC 16:0.

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