Autophagy in osteoblasts is involved in mineralization and bone homeostasis
Résumé
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.
Mots clés
ACP5/TRAP
acid phosphatase 5
tartrate resistant
BECN1
Beclin 1
autophagy-related
BV
bone volume
Baf
bafilomycin A1
Col1A
collagen
type I
α 1
HRTEM
high resolution transmission electron microscopy
MAP1LC3 (LC3)
microtubule-associated protein 1 light chain 3
OB
OC
osteoclast
PBS
phosphate-buffered saline
RNA
ribonucleic acid
RUNX2
runt-related transcription factor 2
SAED
selected area electron diffraction
SPP1/OPN
secreted phosphoprotein 1
TNFSF11/RANKL
tumor necrosis factor (ligand) superfamily
member 11
TUBB
tubulin
beta
TV
total volume
autophagy
bone remodeling
mineralization
osteoblast