Targeting cyclin-dependent kinases in rheumatoid arthritis and psoriasis – a review of current evidence

ABSTRACTIntroduction Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with synovial proliferation and bone erosion, which leads to the structural and functional impairment of the joints. Immune cells, together with synoviocytes, induce a pro-inflammatory environment and novel treatment agents target inflammatory cytokines. Psoriasis is a chronic immune-mediated skin disease, and several cytokines are considered as typical mediators in the progression of the disease, including IL-23, IL-22, and IL-17, among others.Area covered In this review, we try to evaluate whether cyclin-dependent kinases (CDK), enzymes that regulate cell cycle and transcription of various genes, could become novel therapeutic targets in RA and psoriasis. We present the main results of in vitro and in vivo studies, as well as scarce clinical reports.Expert opinion CDK inhibitors seem promising for treating RA and psoriasis because of their multidirectional effects. CDK inhibitors may affect not only the process of osteoclastogenesis, thereby reducing joint destruction in RA, but also the process of apoptosis of neutrophils and macrophages responsible for the development of inflammation in both RA and psoriasis. However, assessing the efficacy of these drugs in clinical practice requires multi-center, long-term clinical trials evaluating the effectiveness and safety of CDK-blocking therapy in RA and psoriasis.KEYWORDS: Cyclin-dependent kinasescyclin-dependent kinase inhibitorspsoriasisRheumatoid arthritisDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsRheumatoid arthritis and psoriasis are common chronic diseases, which are associated with cellular proliferation and inflammation.In RA, inhibition of CDKs can reduce fibroblast-like synoviocytes proliferation, osteoclastogenesis, and induce neutrophil apoptosis.Promotion of CDK inhibitors from INK4 and CIP1 families could become a therapeutic strategy in RA, as stimulation of p16 and p21 expression showed beneficial effects.The use of Palbociclib in breast cancer patients was associated with suppression of rheumatoid arthritis.Inhibition of CDK7 can suppress Th17 responses and reduce IL-17 secretion.Associations between CDKs and histone methyltransferase EZH2 should be further explored, as studies have identified interaction networks with E2F transcription factors, CDK1, CDK2, and CDK4/6.In psoriasis, CDK could become therapeutical targets, but fewer studies with conflicting results have been published.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Figure 1. A: A simplified comparison between the normal and rheumatoid joints. The latter joint is associated with hyperplastic inflamed synovium, bone erosion, and cartilage damage. B: An impact of drugs, compounds, and molecules targeting CDKs on the mechanisms associated with the progression of RA. Inhibition of CDKs suppresses osteoclastogenesis, proliferation and inflammatory responses of fibroblast-like synoviocytes, as well as to promote neutrophil apoptosis. CDK – cyclin dependent kinase; CDKi – cyclin dependent kinase inhibitor; IL- interleukin.Display full sizeFigure 2. CDK pathway and impact of its elements to RA. CDK phosphorylates Rb protein, which in turn de-represses and stimulates E2F transcription factors. Elements and regulators of CDK pathway may promote or suppress the progression of RA. P16 and p21 inhibit RA, while E2F have been found to promote the disease. CDK – cyclin dependent kinase; Rb – retinoblastoma protein; pRb – phosphorylated retinoblastoma protein; PUMA – p53 up-regulated modulator of apoptosisDisplay full sizeFigure 3. A: A simplified and schematic illustration of interactions between dendritic cells, T cells, and keratinocytes in psoriasis. Among other cytokines, dendritic cells secrete IL-12 and IL-23 to induce the differentiation of Th1, Th17, and Th22 cells, which then contribute to the keratinocyte proliferation. B: CDK4/6 phosphorylate EZH2 to induce STAT3 activation. C: CDK7 takes part in Th1 and Th17 responses, critical in the progression of psoriasis. CDK – cyclin dependent kinase; EZH2 - Enhancer of Zeste Homolog 2; IL – interleukin; STAT - signal transducer and activator of transcriptionDisplay full sizeAdditional informationFundingThis paper was not funded,