ADRA2A is involved in neuro‐endocrine regulation of bone resorption

• Published in: Journal of cellular and molecular medicine Vol. 19; no. 7; pp. 1520 - 1529
• Main Authors: Mlakar, Vid, Jurkovic Mlakar, Simona, Zupan, Janja, Komadina, Radko, Prezelj, Janez, Marc, Janja
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Ltd 01.07.2015
• Subjects: ADRA2A; adrenergic signalling; Biomarkers - metabolism; bone; Bone and Bones - metabolism; Bone and Bones - pathology; Bone Remodeling; Bone Resorption - genetics; Bone Resorption - pathology; Bone Resorption - physiopathology; Cell Line, Tumor; Computational Biology; Enzyme Assays; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Luciferases - metabolism; Neurosecretory Systems - metabolism; Neurosecretory Systems - pathology; Original; Osteoarthritis - genetics; Osteoarthritis - pathology; Osteoarthritis - physiopathology; osteoblast; osteoporosis; Osteoporosis - genetics; Osteoporosis - pathology; Osteoporosis - physiopathology; Polymorphism, Single Nucleotide - genetics; Receptors, Adrenergic, alpha-2 - genetics; Receptors, Adrenergic, alpha-2 - metabolism; resorption; resorption; bone; osteoblast; osteoporosis; ADRA2A; adrenergic signalling
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.12505

Adrenergic stimulation is important for osteoclast differentiation and bone resorption. Previous research shows that this happens through β2‐adrenergic receptor (AR), but there are conflicting evidence on presence and role of α2A‐AR in bone. The aim of this study was to investigate the presence of α2A‐AR and its involvement in neuro‐endocrine signalling of bone remodelling in humans. Real‐time polymerase chain reaction (PCR) and immunohistochemistry were used to investigate α2A‐AR receptor presence and localization in bone cells. Functionality of rs553668 and rs1800544 single nucleotide polymorphism SNPs located in α2A‐AR gene was analysed by qPCR expression on bone samples and luciferase reporter assay in human osteosarcoma HOS cells. Using real‐time PCR, genetic association study between rs553668 A>G and rs1800544 C>G SNPs and major bone markers was performed on 661 Slovenian patients with osteoporosis. α2A‐AR is expressed in osteoblasts and lining cells but not in osteocytes. SNP rs553668 has a significant influence on α2A‐AR mRNA level in human bone samples through the stability of mRNA. α2A‐AR gene locus associates with important bone remodelling markers (BMD, CTX, Cathepsin K and pOC). The results of this study are providing comprehensive new evidence that α2A‐AR is involved in neuro‐endocrine signalling of bone turnover and development of osteoporosis. As shown by our results the neurological signalling is mediated through osteoblasts and result in bone resorption. Genetic study showed association of SNPs in α2A‐AR gene locus with bone remodelling markers, identifying the individuals with higher risk of development of osteoporosis.