Rheumatoid arthritis (RA) is a chronic and systemic autoimmune inflammatory disease associated with pain, synovial hyperplasia, cartilage destruction and functional disability in most patients. A lot of different pathways participates in the pathogenesis of RA. Specifically, pro-inflammatory cytokines, including tumor necrosis factor-alfa (TNF-¿), interleukin-1 beta (IL-1ß) and IL-6 play key roles in RA.
PK2 is a new chemokine that acting on two G-protein linked receptors, prokineticin receptor 1 and 2 (PKR1 and PKR2), modulates the nociceptive threshold and is involved in immuno-inflammatory processes. We have already demonstrated that the prokineticin system (PK) plays a role in animal models of inflammatory and neuropathic pain and we also demonstrated that the pharmacological blockade of this system not only relieves pain, but also ameliorates the pathological processes underlying pain. Moreover, recently the involvement of PK2 and PKR2 in the pathogenesis of type II collagen-induced arthritis in mice was reported. These data suggest that blocking PKRs might be a winning strategy in controlling of arthritic pain and pathology development.
Based on these considerations, the project aims to evaluate the role of the PK2/PKRs in the type II collagen (CII)-induced arthritis (CIA) and whether therapeutic treatment with a non-peptide PKR antagonist, PC1, might be useful in controlling arthritic pain and possibly the pathological processes underlying pain.
Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects approximately 1% of the adult population worldwide. Chronic or episodic pain is a frequent problem for this group of patients and it contributes to the loss of joint mobility and causes both psychological distress and impaired quality of life. In spite of significant improvements in the treatment of RA there is still a need for the identification of new pathways involved in the modulation of inflammation in order to further increase the efficacy of treatment, particularly in patients in whom the disease does not respond to current therapies [1, 2].
The involvement of a the new chemokine, known as Bv8 or prokineticin2 (PK2) has been suggested in the pathogenesis of type II collagen-induced arthritis (CIA) in mice [3]. Indeed, Ito et al recently demonstrated that PK2 and PKR2 gene expression levels were elevated in the CIA joints [4]. Moreover, we have already demonstrate the involvement of the prokineticin system in animal models of inflammatory and neuropathic pain and we also demonstrated that the pharmacological blockade of this system not only relieves pain but also ameliorates the pathological processes underlying pain [5, 6, 7, 8]. All these data are identifying PK2 and its receptors as novel potential therapeutic targets for analgesic, antiinflammatory and immunomodulatory drug development.
Therefore, given the availability, in our group, of PKR antagonists, which demonstrated to be highly effective not only in controlling pain but also the inflammatory processes, in this project, PKR antagonist PC1 will be tested as innovative drug to combat arthritic inflammation and pain.
[1] Walsh & McWilliams 2012. Curr Pain Headache Rep 16:509.
[2] Scott et al. 2010. Lancet 376:1094.
[3] Kurosaka et al. 2009. BMC Musculoskel Disord 10:45.
[4] Ito et al. 2016. BMC Musculoskelet Disord 17: 387.
[5]Giannini et al. 2009. PNAS 106: 14646.
[6] Maftei et al. 2014. Br J Pharmacol 171: 4850.
[7] Lattanzi et al. 2015. Biomed Res Int 5: 5064.
[8] Guida et al. 2015. Pharmacol Res 91: 36.