Abstract
The mitochondrial sirtuin 3 (SIRT3) is involved in suppressing the onset of multiple pathologies, including cardiovascular disease, fatty liver, age-related hearing loss, and breast cancer. But a physiological role of SIRT3 in bone metabolism is not known. Here we show that SIRT3 is a key regulatory molecule to maintain bone homeostasis. Mice deficient in SIRT3 exhibited severe osteopenia owing to increased numbers of osteoclasts. Osteoclast precursors from Sirt3−/− mice underwent increased osteoclastogenesis in response to receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclast differentiation. SIRT3 expression from RANKL induction depended on the transcription coactivator PGC-1β (peroxisome proliferator-activated receptor-γ co-activator-1β) and the nuclear receptor ERRα (estrogen receptor-related receptor α), and that SIRT3 inhibited the differentiation by interfering with the RANKL-induced expression of PGC-1β. Thus an auto-regulatory feedback mechanism operates to induce its own inhibitor SIRT3 by PGC-1β. Moreover, Sirt3−/− osteoclast precursors reduced AMP-activated protein kinase (AMPK) phosphorylation through down-regulating the expression of AMPK. Our results suggest that a mitochondrial SIRT3 is an intrinsic inhibitor for RANKL-mediated osteoclastogenesis.
Highlights
Bone remodeling depends on a delicate balance between bone resorption and bone formation, wherein bone-resorbing osteoclasts and bone-forming osteoblasts play essential roles[1]
Since sirtuin 3 (SIRT3) is known to promote mitochondrial biogenesis[14,15], which plays a critical role in osteoclast formation[25,26], we investigated the role of SIRT3 in osteoclasts in vivo
Though SIRT3 as a major mitochondrial deacetylase has been well documented to have a variety of mitochondrial functions such as energy production, ROS homeostasis, and mitochondrial biogenesis in several tissues[17,23,24], the role of SIRT3 in osteoclast differentiation remains unexplored
Summary
Bone remodeling depends on a delicate balance between bone resorption and bone formation, wherein bone-resorbing osteoclasts and bone-forming osteoblasts play essential roles[1]. SIRT3 deacetylates many proteins and regulates their activities, which are involved with mitochondrial biogenesis, ROS homeostasis, and metabolic pathways in mitochondria[14,15,16]. The physiological roles of SIRT3 in several organs in mammal have been extensively documented with respect to mitochondrial metabolism[22,23,24] It is still unknown whether SIRT3 is involved in bone homeostasis. SIRT3 was induced by PGC-1β together with ERRα during RANKL-induced osteoclast differentiation, and it may function as a negative mediator for osteoclastogenesis through stabilization of AMPK protein. Our data suggest that SIRT3 plays an important role as a molecular brake on excessive osteoclastogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
