title: The role of the BH3-only protein Noxa in bone homeostasis.
abstract: Bone homeostasis is maintained by a dynamic balance between bone resorption by osteoclasts and bone formation by osteoblasts. Since excessive osteoclast activity is implicated in pathological bone resorption, understanding the mechanism underlying osteoclast differentiation, function and survival is of both scientific and clinical importance. Osteoclasts are monocyte/macrophage lineage cells with a short life span that undergo rapid apoptosis, the rate of which critically determines the level of bone resorption in vivo. However, the molecular basis of rapid osteoclast apoptosis remains obscure. Here we report the role of a BH3-only protein, Noxa (encoded by the Pmaip1 gene), in bone homeostasis using Noxa-deficient mice. Among the Bcl-2 family members, Noxa was selectively induced during osteoclastogenesis. Mice lacking Noxa exhibit a severe osteoporotic phenotype due to an increased number of osteoclasts. Noxa deficiency did not have any effect on the number of osteoclast precursor cells or the expression of osteoclast-specific genes, but led to a prolonged survival of osteoclasts. Furthermore, adenovirus-mediated Noxa overexpression remarkably reduced bone loss in a model of inflammation-induced bone destruction. This study reveals Noxa to be a crucial regulator of osteoclast apoptosis, and may provide a molecular basis for a new therapeutic approach to bone diseases.
authors.affiliation: Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Tokyo 113-8549, Japan.
authors.forename: Erik
authors.initials: E
authors.lastname: Idrus
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakashima
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Mikihito
authors.initials: M
authors.lastname: Hayashi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okamoto
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001842:Bone and Bones / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D051379:Mice; D008817:Mice, Mutant Strains; D010010:Osteoclasts / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*
chemical_list: C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2