title: Noxa in rheumatic diseases: present understanding and future impact.
abstract: Impaired programmed cell death is an important contributing mechanism in the development of chronic inflammatory and autoimmune diseases. Overexpression of Bcl-2 family proteins in such diseases has led to the concept of targeted suppression of these proteins as a primary therapeutic strategy. However, limited success with this approach has prompted pharmacologists to look at the other side of the coin, with the aim of reactivating jeopardized pro-apoptotic proteins that may neutralize Bcl-2 or other anti-apoptotic molecules. In this effort, BH3-only proteins have gained recent attention as endogenous molecules for the sensitization of resistant cells to undergo apoptosis. Among the BH3-only family, Noxa stands out as exceptional for its specificity to bind Mcl-1 and Bcl-2 and blunt their biological properties. Noxa is now being tested as a promising therapeutic target in cancer biology. Nonetheless, its role and clinical application still lack validation in autoimmune diseases, including rheumatic conditions. This is partly attributed to the significant gap in our understanding of its regulatory role and how either overexpression of Noxa or delivery of BH3 mimetics could be therapeutically exploited. In this review we highlight some recent studies in RA, OA, SLE and SS suggesting that Noxa may be used as a potential therapeutic target to circumvent invasive and tissue destructive processes in these rheumatic diseases.
authors.affiliation: Department of Pharmacology, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH and Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Karissa E
authors.initials: KE
authors.lastname: Cottier
authors.affiliation: Department of Pharmacology, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH and Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Elise M
authors.initials: EM
authors.lastname: Fogle
authors.affiliation: Department of Pharmacology, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH and Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fox
authors.affiliation: Department of Pharmacology, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, OH and Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. Salah.Ahmed@utoledo.edu.
authors.forename: Salahuddin
authors.initials: S
authors.lastname: Ahmed
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D040761:Biomimetic Materials / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods* / Q000639:trends; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology*; D012216:Rheumatic Diseases / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology
chemical_list: D018501:Antirheumatic Agents; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: BH3-only proteins; Bcl-2; Mcl-1; Noxa; Sjögren’s syndrome; apoptosis; osteoarthritis; rheumatoid arthritis; therapeutics