JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production

Abstract

Objective. The mechanistic link between Janus kinase (JAK) signaling and structural damage to arthritic joints in rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate how selective inhibition of JAK with tofacitinib (CP-690,550) affects osteoclast-mediated bone resorption in a rat adjuvant-induced arthritis (AIA) model, as well as human T lymphocyte RANKL production and human osteoclast differentiation and function.Methods. Hind paw edema, inflammatory cell infiltration, and osteoclast-mediated bone resorption in rat AIA were assessed using plethysmography, histopathologic analysis, and immunohistochemistry; plasma and hind paw tissue levels of cytokines and chemokines (including RANKL) were also assessed. In vitro RANKL production by activated human T lymphocytes was evaluated by immunoassay, while human osteoclast differentiation and function were assessed via quantitative tartrate-resistant acid phosphatase staining and degradation of human bone collagen, respectively.Results. Edema, inflammation, and osteoclastmediated bone resorption in rats with AIA were dramatically reduced after 7 days of treatment with the JAK inhibitor, which correlated with reduced numbers of CD68/ED-1؉, CD3؉, and RANKL؉ cells in the paws; interleukin-6 (transcript and protein) levels were rapidly reduced in paw tissue within 4 hours of the first dose, whereas it took 4-7 days of therapy for RANKL levels to decrease. Tofacitinib did not impact human osteoclast differentiation or function, but did decrease human T lymphocyte RANKL production in a concentration-dependent manner.Conclusion. These results suggest that the JAK inhibitor tofacitinib suppresses osteoclast-mediated structural damage to arthritic joints, and this effect is secondary to decreased RANKL production.

Preclinical to Clinical Translation of Tofacitinib, a Janus Kinase Inhibitor, in Rheumatoid Arthritis

“…Single-dose tofacitinib data in mCIA demonstrated immediate effects of tofacitinib on plasma inflammatory mediators and in some cases sustained impact on chemotactic proteins, without an immediate bearing on the disease severity index. Rapid inhibition of IL-6, IP-10, and other inflammatory mediators has previously been demonstrated in mCIA and rat adjuvantinduced arthritis, and likely represents blockade of innate immune mechanisms (Ghoreschi et al, 2011;LaBranche et al, 2012). Sustained effects on innate immunity following tofacitinib administration would be consistent with a mechanism of prolonged modulation of transcriptional activity downstream of JAK signaling.…”

“…Studies in animal models of arthritis have indicated that JAK inhibition reduces signs and histologic manifestations of arthritis (Milici et al, 2006(Milici et al, , 2008Lin et al, 2010;Fridman et al, 2010). More specifically, tofacitinib treatment resulted in dose-dependent reduction in joint inflammation in mouse and rat arthritis models (Milici et al, 2008;Meyer et al, 2010;Ghoreschi et al, 2011;LaBranche et al, 2012). JAK inhibition by tofacitinib blocks signaling through the common g chain-containing receptors for several cytokines, including interleukin (IL)-2, -4, -7, -9, -15, and -21, and through receptors for cytokines such as IL-6, interferon-g (IFN-g), and type 1 IFN (Meyer et al, 2010;Ghoreschi et al, 2011).…”

JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T Cells and Th17 Cells

“…Maeshima et al (16) suggested that the therapeutic effect of tofacitinib results from inhibition of IFN-g and IL-17A. LaBranche et al (17) reported that tofacitinib suppressed arthritic joint structural damage by decreasing RANKL production.…”

“…Tofacitinib (CP-690,550), a pan-JAK inhibitor that is currently in use for the treatment of RA, was shown to suppress the production of IL-17 and IFN-g, as well as the proliferation of CD4 + T cells, under conditions of anti-CD3 and anti-CD28 stimulation (16), and to decrease T lymphocyte receptor activator for NF-kB ligand (RANKL) production (17). However, pan-JAK inhibitors may have safety issues linked to "off-target" effects, because JAK proteins are essential in signaling pathways that maintain physiological immune responses and processes, including hematopoiesis (18).…”

Liquid chromatographic-tandem mass spectrometric assay for simultaneous quantitation of tofacitinib, cabozantinib and afatinib in human plasma and urine

“…The last chosen kinase inhibitor is tofacitinib (TOF; Figure 1c), which is a representative of the Janus kinase inhibitors (JAKIs). TOF is reported to selectively block the signaling pathway involving the kinases JAK 1 and 3 [8]. TOF was approved by the U.S. FDA in 2012 for the management of patients with moderate to severe rheumatoid arthritis (RA) either alone or to be taken with methotrexate in more sever un-responsive cases [9].…”