NHA-oc/NHA2: a mitochondrial cation-proton antiporter selectively expressed in osteoclasts.
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.
Battaglino
R A
RA
Department of Cytokine Biology, Forsyth Institute, 140 The Fenway, Boston, MA 02115, USA. rbattaglino@forsyth.org
Pham
L
L
Morse
L R
LR
Vokes
M
M
Sharma
A
A
Odgren
P R
PR
Yang
M
M
Sasaki
H
H
Stashenko
P
P
D000595:Amino Acid Sequence; D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D003001:Cloning, Molecular; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008933:Mitochondrial Swelling; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
D017920:Antiporters; C526786:NHA2 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C527589:SLC9B2 protein, human; D020169:Caspases