title: Serum Metabolite Profiles Are Altered by Erlotinib Treatment and the Integrin α1-Null Genotype but Not by Post-Traumatic Osteoarthritis.
abstract: The risk of developing post-traumatic osteoarthritis (PTOA) following joint injury is high. Furthering our understanding of the molecular mechanisms underlying PTOA and/or identifying novel biomarkers for early detection may help to improve treatment outcomes. Increased expression of integrin α1β1 and inhibition of epidermal growth factor receptor (EGFR) signaling protect the knee from spontaneous OA; however, the impact of the integrin α1β1/EGFR axis on PTOA is currently unknown. We sought to determine metabolic changes in serum samples collected from wild-type and integrin α1-null mice that underwent surgery to destabilize the medial meniscus and were treated with the EGFR inhibitor erlotinib. Following (1)H nuclear magnetic resonance spectroscopy, we generated multivariate statistical models that distinguished between the metabolic profiles of erlotinib- versus vehicle-treated mice and the integrin α1-null versus wild-type mouse genotype. Our results show the sex-dependent effects of erlotinib treatment and highlight glutamine as a metabolite that counteracts this treatment. Furthermore, we identified a set of metabolites associated with increased reactive oxygen species production, susceptibility to OA, and regulation of TRP channels in α1-null mice. Our study indicates that systemic pharmacological and genetic factors have a greater effect on serum metabolic profiles than site-specific factors such as surgery.
authors.forename: Beata
authors.initials: B
authors.lastname: Mickiewicz
authors.forename: Sung Y
authors.initials: SY
authors.lastname: Shin
authors.affiliation: Department of Medicine, Vanderbilt University , Nashville, Tennessee 37232, United States.|Department of Medicine, Veterans Affairs Hospital , Nashville, Tennessee 37232, United States.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Vogel
authors.affiliation: Department of Surgery, Cumming School of Medicine, University of Calgary , Calgary T2N 4N1, AB, Canada.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Clark
mesh_terms: D000818:Animals; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D039423:Integrin alpha1 / Q000235:genetics*; D008297:Male; D008592:Menisci, Tibial / Q000601:surgery; D055442:Metabolome / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020370:Osteoarthritis, Knee / Q000097:blood* / Q000188:drug therapy; D017382:Reactive Oxygen Species; D050051:Transient Receptor Potential Channels
chemical_list: D039423:Integrin alpha1; D017382:Reactive Oxygen Species; D050051:Transient Receptor Potential Channels; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors
keywords: 1H nuclear magnetic resonance spectroscopy; Post-traumatic osteoarthritis; destabilization of the medial meniscus; erlotinib; integrin α1β1; metabolomics; mice; multivariate statistical analysis