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Abnormal Response of Costal Chondrocytes to Acidosis in Patients with Chest Wall Deformity

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Abnormal Response of Costal Chondrocytes to Acidosis in Patients with Chest Wall Deformity Old Dominion University ODU Digital Commons Bioelectrics Publications Frank Reidy Research Center for Bioelectrics 2019 Abnormal Response of Costal Chondrocytes to Acidosis in Patients with Chest Wall Deformity A. Asmar Old Dominion University, [email protected] Iurii Semenov Old Dominion University, [email protected] R. Kelly Jr. Eastern Virginia Medical School Michael Stacey Old Dominion University, [email protected] Follow this and additional works at: https://digitalcommons.odu.edu/bioelectrics_pubs Part of the Cells Commons, Genetic Phenomena Commons, and the Musculoskeletal System Commons Original Publication Citation Asmar, A., Semenov, I., Kelly, R., & Stacey, M. (2019). Abnormal response of costal chondrocytes to acidosis in patients with chest wall deformity. Experimental and Molecular Pathology, 106, 27-33. https://doi.org/10.1016/j.yexmp.2018.11.011 This Article is brought to you for free and open access by the Frank Reidy Research Center for Bioelectrics at ODU Digital Commons. It has been accepted for inclusion in Bioelectrics Publications by an authorized administrator of ODU Digital Commons. For more information, please contact [email protected]. Experimental and Molecular Pathology 106 (2019) 27–33 Contents lists available at ScienceDirect Experimental and Molecular Pathology journal homepage: www.elsevier.com/locate/yexmp Abnormal response of costal chondrocytes to acidosis in patients with chest wall deformity T ⁎ A. Asmara, I. Semenova, R. Kelly Jrb, M. Staceya, a Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA b Department of Surgery, Eastern Virginia Medical School, Pediatric Surgery Division, Children's Hospital of the King's Daughters, Norfolk, VA, USA ARTICLE INFO ABSTRACT Keywords: Costal cartilage is much understudied compared to the load bearing cartilages. Abnormally grown costal car- Cartilage tilages are associated with the inherited chest wall deformities pectus excavatum and pectus carinatum resulting Chondrocytes in sunken or pigeon chest respectively. A lack of understanding of the ultrastructural and molecular biology Ion channels properties of costal cartilage is a major confounder in predicting causes and outcomes of these disorders. Due to Calcium the avascular nature of cartilage, chondrocytes metabolize glycolytically, producing an acidic environment. Pectus carinatum During physical activity hydrogen ions move within cartilage driven by compressive forces, thus at any one time, Pectus excavatum chondrocytes experience transient changes in pH. A variety of ion channels on chondrocytes plasma membrane equip them to function in the rapidly changing conditions they experience. In this paper we describe reduced expression of the ASIC2 gene encoding the acid sensing ion channel isoform 2 (previously referred to as ACCN1 or ACCN) in patients with chest wall deformities. We hypothesized that chondrocytes from these patients cannot respond normally to changes in pH that are an integral part of the biology of this tissue. Activation of ASICs indirectly creates a cascade ultimately dependent on intracellular calcium transients. The objective of this paper was to compare internal calcium signaling in response to external pH changes in costal chondrocytes from patients with chest wall deformities and healthy individuals. Although the molecular mechanism through which chondrocytes are regulated by acidosis remains unknown, we observed reduced amplitudes of calcium rise in patient chondrocytes exposed to low pH that become further impaired upon repeat exposure. 1. Introduction bar displacements dropped significantly. Safety concerns regarding the absorption of electro-magnetic (EM) energy (specific energy absorption Chest wall deformities (CWD) are significant disorders of costal rate; SAR) by the implanted bar arose due to the length of time the bars cartilage and a leading health problem affecting young adults. CWD are in place. This was addressed by Miaskowski et al. (2016) whose patients are often described as having ‘weak’ cartilage and typically results clearly indicated that a conductive object, such as a concave face exercise intolerance due to associated heart and lung limitations, in implant may cause possible local enhancement of power absorption and addition to substantial psychosocial problems in a vulnerable age group produce characteristic SAR peaks around the bar-implant. However, the (Kelly Jr. et al., 2013). In severe cases where access to proper reparative obtained maximum SAR values did not exceed the recommended re- surgery is unavailable, marked functional consequences may be en- ference levels for environmental and occupational exposures. countered. CWD are a complex inherited disorder affecting 1 in 400 to 1 Chondrocytes, the cartilage forming cells, reside under an en- in 1000 individuals, primarily males (~4M:1F) (Creswick et al., 2006; vironment that is toxic to most cell types due to a lack of vasculature, Horth et al., 2012) and can be divided into those with sunken chests persistent hypoxia, and related acid production through glycolytic (pectus excavatum, PE) and those with pigeon chests (pectus car- metabolism. In other cell types low pH activates a unique family of inatum, PC). Repair of PE is now routinely performed following the membrane ion channels; the acid-sensing ion channels (ASICs) (Chu minimally invasive Nuss procedure (Nuss, 2008, Pilegaard and Licht, et al., 2011). In pathological conditions of articular cartilage such as 2017) where one or two substernal support titanium bars are inserted osteoarthritis and rheumatoid arthritis, the tissue pH become acidic, and kept in place for approximately 2–3 years. Outcomes are reported falling to approximately pH 5.5 (Hu et al., 2012). In this paper we de- as excellent (Goretsky et al., 2004). With the introduction of stabilizers, scribe reduced expression of the ASIC2 gene in patients with chest wall ⁎ Corresponding author at: Frank Reidy Research Center for Bioelectrics, 4211 Monarch Way, Suite 300, Norfolk, VA 23508, USA. E-mail address: [email protected] (M. Stacey). https://doi.org/10.1016/j.yexmp.2018.11.011 Received 21 May 2018; Received in revised form 8 November 2018; Accepted 24 November 2018 Available online 25 November 2018 0014-4800/ © 2018 Elsevier Inc. All rights reserved. A. Asmar et al. Experimental and Molecular Pathology 106 (2019) 27–33 deformities. We hypothesized that chondrocytes from these patients exhibit an abnormal response to changes in external pH that are ex- perienced as an integral part of the biology of this tissue. Activation of ASICs typically creates a cascade ultimately dependent on the forma- tion of intracellular calcium transients. Changes in intracellular calcium signaling cause downstream changes in gene expression. An excessive amount of intracellular calcium induces cell death through apoptosis in chondrocytes (Rong et al., 2012; Li et al., 2014; Zhou et al., 2015). Low pH is known to cause a decrease in extra cellular matrix (ECM) pro- duction (Yuan et al., 2010). The objective of this study was to measure intracellular calcium changes in response to reducing environmental pH around costal chondrocytes from patients with CWD. 2. Methods Fig. 1. Median fold changes in non-selective ion channels in chondrocytes of CWD patients using qPCR. Pectus excavatum (PE; purple box plot) and pectus 2.1. Patients carinatum (PC; blue box plot) are shown relative to normal costal cartilage. Each sample was analyzed with an n = 3 and significant changes (p < .05) relative to normal costal cartilage are indicated (*). The green and red hor- Human costal cartilage was obtained from three patients with izontal lines indicated a +2 or −2 fold change, respectively. Outlying data pectus carinatum and three with pectus excavatum, all severe enough points in PC patients are indicated by unconnected orange dots. Genes analyzed to warrant surgical repair. Informed consent was obtained following are ASIC1, 2, and 3 Acid Sensing Ion Channel unit 1, 2, and 3; BCNG2 (HCN2) IRB approval of the protocol at Eastern Virginia Medical School and Old Hyperpolarization Activated Cyclic Nucleotide Gated Potassium and Sodium Dominion University. The IRB protocol currently prevents disclosure of Channel 2; BEST1 Bestrophin; TRPC1 Transient Receptor Potential Cation many clinical features, and thus close correlation of clinical phenotype Channel Subfamily C Member 1; TRPV1–4 Transient Receptor Potential Cation with gene expression is not possible. Costal cartilage samples were Channel Subfamily V Members 1–4. (For interpretation of the references to collected from ribs 6–8 at surgery. Experiments were performed on the colour in this figure legend, the reader is referred to the web version of this round, rod-like, midsections of cartilage. All patients were male, with article.) an age range of early teen to early 20's. Apparently normal costal car- tilage was obtained from three age-matched-controls, one 15 year old 2.3. Protein extraction and ELISA and two 17-year-old males, and processed within 24 h. Cells were cul- tured in Chondrocyte growth medium (PromoCell) at 37 °C with 5% Protein was isolated from chondrocytes grown in 3D as cell pellets CO2 in humidified air. Chondrocytes were maintained in suspension by rinsing the cells in cold PBS three times, centrifuged at 300 ×g for culture (Bosnakovski et al., 2004; Wa et al., 2015) to maintain their 10 min at 4 °C. RIPA buffer (Sigma) with protease inhibitors (Roche) differentiated phenotype, and briefly expanded in tissue culture
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