NHA-oc/NHA2: A mitochondrial cation–proton antiporter selectively expressed in osteoclasts

• Published in: Bone (New York, N.Y.) N.Y.), 2008-01, Vol.42 (1), p.180-192
• Main Authors: Battaglino, R.A, Pham, L, Morse, L.R, Vokes, M, Sharma, A, Odgren, P.R, Yang, M, Sasaki, H, Stashenko, P
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antiporter; Antiporters - genetics; Antiporters - metabolism; Biological and medical sciences; Caspases - metabolism; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; Cloning, Molecular; Diseases of the osteoarticular system; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Humans; Hydrogen-Ion Concentration; Medical sciences; Mice; Mitochondria; Mitochondria - metabolism; Mitochondrial Swelling; Molecular and cellular biology; Molecular Sequence Data; Orthopedics; Osteoclast; Osteoclasts - cytology; Osteoclasts - metabolism; Proton; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Sodium; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2007.09.046

Abstract Bone resorption is regulated by a complex system of hormones and cytokines that cause osteoblasts/stromal cells and lymphocytes to produce factors including RANKL, that ultimately result in the differentiation and activation of osteoclasts, the bone resorbing cells. We used a microarray approach to identify genes upregulated in RANKL-stimulated osteoclast precursor cells. Osteoclast expression was confirmed by multiple tissue Northern and in situ hybridization analysis. Gene function studies were carried out by siRNA analysis. We identified a novel gene, which we termed nha-oc/NHA2 , which is strongly upregulated during RANKL-induced osteoclast differentiation in vitro and in vivo. nha-oc/NHA2 encodes a novel cation–proton antiporter (CPA) and is the mouse orthologue of a human gene identified in a database search: HsNHA2. nha-oc/NHA2 is selectively expressed in osteoclasts. NHA-oc/NHA2 protein localizes to the mitochondria, where it mediates Na+ -dependent changes in mitochondrial pH and Na+ acetate induced mitochondrial passive swelling. RNA silencing of nha-oc/nha2 reduces osteoclast differentiation and resorption, suggesting a role for NHA-oc/NHA2 in these processes. nha-oc/NHA2 therefore is a novel member of the CPA family and is the first mitochondrial NHA characterized to date. nha-oc/NHA2 is also unique in that it is the first eukaryotic and tissue-specific CPA2 characterized to date. NHA-oc/NHA2 displays the expected activities of a bona fide CPA and plays a key role(s) in normal osteoclast differentiation and function.