Article Text

Download PDFPDF

FRI0131 ELUCIDATING THE MECHANISM UNDERLYING CREATINE PHOSPHOKINASE UPREGULATION WITH UPADACITINIB
Free
  1. Kara Queeney1,
  2. William Housley1,
  3. Jeremy Sokolov2,
  4. Andrew Long1
  1. 1AbbVie, Pharmacology, Worcester, United States of America
  2. 2AbbVie, Clinical Development, Redwood City, United States of America

Abstract

Background: JAK inhibitors, including Upadacitinib (UPA), have been associated with increased serum levels of creatine phosphokinase (CPK) in patients with inflammatory disorders, but not in patients with myeloproliferative disease or in healthy subjects treated for a limited duration (1). While CPK increases can be indicative of muscle damage, there are no other indicators of muscle pathology observed with JAK inhibitors, suggesting that there may be another mechanism behind the increased CPK levels. Inflammatory diseases including rheumatoid arthritis are often associated with reduced muscle mass (sarcopenia), a process reversed with disease control (2).

Objectives: We hypothesized that one or more cytokines present in the inflammatory milieu may block differentiation of myoblasts into mature myocytes and that JAK inhibition restores differentiation and associated CPK expression. We focused on the gp130-mediated cytokines IL6, Oncostatin M (OSM), CNTF, and LIF as these have been shown to impact myoblast differentiation.

Methods: Human skeletal muscle myoblast (HSMM) cells were cultured in 10% fetal bovine serum, or were serum starved (2% horse serum) to induce differentiation into myocytes, with and without stimulation with OSM (1–100 ng/ml) and/or UPA (0.0007–1 μM) for up to 5 days. RNA was purified and expression of CPK (M-type) was determined by QPCR using GAPDH as a reference. CPK expression was also measured following stimulation of HSMM cells with other JAK inhibitors (Baricitinib and Tofacitinib).

Results: We have demonstrated that the gp130-mediated cytokine oncostatin M blocks myoblast differentiation into myotubules resulting in a decrease in CPK expression. Jak inhibition restores muscle differentiation and increased CPK expression (Figure 1A). Oncostatin M is highly expressed in RA synovium and other inflammatory milieu and may be one mechanism driving sarcopenia in RA. In addition to Upadacitinib, both Baricitinib and Tofacitinib restore myoblast differentiation suggesting that this is a class effect for JAK inhibitors (Figure 1B).

Conclusion: Our studies suggest that the increase in serum CPK upon treatment with JAK inhibitors may represent recovery of muscle development via reversal of inflammation-associated inhibition of myoblast differentiation

References: [1] J. D. Isaacs, et al., Arthritis Res Ther 16, R158 (2014).

[2] J. T. Giles, et al.,. Arthritis Rheum 59, 807-815 (2008).

Figure 1

JAK inhibitors result in increased CPK expression in the presence of OSM. (A) M-type CPK mRNA expression in HSMM cells stimulated with OSM (100 ng/mL) and/or UPA (0.0007–1 μM) for 24 hours. (B) M-type CPK mRNA expression in HSMM cells stimulated with OSM (100 ng/mL) and UPA, Baricitinib, or Tofacitinib for 24 hours. Data is represented as a mean +/- Standard deviation. One representative is shown of 3 from two donors. CM, 10% FBS media; Diff, 2% Horse serum differentiation media; OSM, oncostatin M;UPA, Upadacitinib; CKM, creatine kinase M-type. HSMM, human skeletal muscle myoblasts.

Disclosure of Interests: Kara Queeney Shareholder of: Kara Queeney is an employee of AbbVie and may hold stock or options, Employee of: Kara Queeney is an employee of AbbVie and may hold stock or options, William Housley Shareholder of: Will Housley is an employee of AbbVie and may hold stock or options, Employee of: Will Housley is an employee of AbbVie and may hold stock or options, Jeremy Sokolov Shareholder of: Jeremy Sokolov is an employee of AbbVie and may hold stock or options, Employee of: Jeremy Sokolov is an employee of AbbVie and may hold stock or options, Andrew Long Shareholder of: Andrew Long is an employee of AbbVie and may hold stock or options, Employee of: Andrew Long is an employee of AbbVie and may hold stock or options

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.