Abstract
Bone remodeling is a tightly controlled mechanism in which osteoblasts (OB), the cells responsible for bone formation, osteoclasts (OC), the cells specialized for bone resorption, and osteocytes, the multifunctional mechanosensing cells embedded in the bone matrix, are the main actors. Increased oxidative stress in OB, the cells producing and mineralizing bone matrix, has been associated with osteoporosis development but the role of autophagy in OB has not yet been addressed. This is the goal of the present study. We first show that the autophagic process is induced in OB during mineralization. Then, using knockdown of autophagy-essential genes and OB-specific autophagy-deficient mice, we demonstrate that autophagy deficiency reduces mineralization capacity. Moreover, our data suggest that autophagic vacuoles could be used as vehicles in OB to secrete apatite crystals. In addition, autophagy-deficient OB exhibit increased oxidative stress and secretion of the receptor activator of NFKB1 (TNFSF11/RANKL), favoring generation of OC, the cells specialized in bone resorption. In vivo, we observed a 50% reduction in trabecular bone mass in OB-specific autophagy-deficient mice. Taken together, our results show for the first time that autophagy in OB is involved both in the mineralization process and in bone homeostasis. These findings are of importance for mineralized tissues which extend from corals to vertebrates and uncover new therapeutic targets for calcified tissue-related metabolic pathologies.
Highlights
Bone remodeling is a tightly controlled mechanism in which osteoblasts (OB), the cells responsible for bone formation, osteoclasts (OC), the cells specialized for bone resorption, and osteocytes, the multifunctional mechanosensing cells embedded in the bone matrix, are the main actors.[1]
BaÞlomycin-A1Ðtreated cells, LC3-II levels were further increased at each time point, suggesting that mineralization is associated with enhanced autophagosome formation
At day 5, we observed a global decrease of the GFP signal, associated with the appearance of autophagic cells, especially in the vicinity of the mineralization foci, conÞrming autophagy induction during mineralization
Summary
Bone remodeling is a tightly controlled mechanism in which osteoblasts (OB), the cells responsible for bone formation, osteoclasts (OC), the cells specialized for bone resorption, and osteocytes, the multifunctional mechanosensing cells embedded in the bone matrix, are the main actors.[1]. 3. Autophagy is the major catabolic process of eukaryotic cells that degrades and recycles damaged macromolecules and organelles.[4,5] During this process, the cytoplasmic material targeted to degradation is delivered to lysosomes upon sequestration within doublemembraned vesicles that are called autophagosomes. Autophagy is the major catabolic process of eukaryotic cells that degrades and recycles damaged macromolecules and organelles.[4,5] During this process, the cytoplasmic material targeted to degradation is delivered to lysosomes upon sequestration within doublemembraned vesicles that are called autophagosomes Autophagosomes and their contents are cleared upon fusing with late endosomes or lysosomes, and products of these catabolic reactions can re-enter anabolic and/or bioenergetic metabolisms.[4,6] Autophagy occurs at low level in all cells to ensure the homeostatic turnover of long-lived proteins and organelles[7] and is upregulated under stressfull conditions. Autophagosomes and their contents are cleared upon fusing with late endosomes or lysosomes, and products of these catabolic reactions can re-enter anabolic and/or bioenergetic metabolisms.[4,6] Autophagy occurs at low level in all cells to ensure the homeostatic turnover of long-lived proteins and organelles[7] and is upregulated under stressfull conditions. 8
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