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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.

Osteoclasts are the cells responsible for physiological bone resorption. A specific organization of their most prominent cytoskeletal structures, podosomes, is crucial for the degradation of mineralized bone matrix. Each podosome is constituted of an F-actin-enriched central core surrounded by a loose F-actin network, called the podosome cloud. In addition to intrinsic actin dynamics, podosomes are defined by their adhesion to the extracellular matrix, mainly via core-linking CD44 and cloud-linking integrins. These properties allow podosomes to collectively evolve into different patterns implicated in migration and bone resorption. Indeed, to resorb bone, osteoclasts polarize, actively secrete protons, and proteases into the resorption pit where these molecules are confined by a podosome-containing sealing zone. Here, we review recent advancements on podosome structure and regulatory pathways in osteoclasts. We also discuss the distinct functions of different podosome patterns during the lifespan of a single osteoclast.

Two-step transcriptomic profiling of bone-resorbing OCs versus nonresorbing MGCs generated a list of 115 genes potentially involved in bone resorption. Of these, RhoE was investigated. Its role in podosome dynamics is central for OC migration, SZ formation, and, ultimately, bone resorption.

Podosomes are dynamic, actin-containing adhesion structures that self-organize as rings in osteoclasts. We observe that podosome rings generate tension forces and that osteoclasts migrate by periodically moving toward the actin-containing structures. Actin dynamics thus not only correlate with the cell migration, but drive it.

Survival and capability of cancer cells to form metastases fundamentally depend on interactions with their microenvironment. Secondary tumors originating from prostate carcinomas affect remodeling of bone tissue and can induce both osteolytic and osteocondensing lesions. However, particular molecular mechanisms responsible for selective homing and activity of cancer cells in bone microenvironment have not been clarified yet. Growth/differentiation factor-15 (GDF-15), a distant member of the TGF-β protein family, has recently been associated with many human cancers, including prostate.

L’interface entre le système immunitaire et la physiologie osseuse a conduit à l’émergence de l’ostéo-immunologie, nouveau champ de recherche qui ouvre de nouvelles perspectives dans la compréhension et le traitement des pathologies inflammatoires ostéo-articulaires. De nombreuses molécules et voies de signalisation, décrites initialement dans les cellules du système immunitaire, agissent également dans les ostéoclastes, cellules ayant pour rôle le maintien de l’homéostasie osseuse en assurant le remodelage du tissu osseux. Ainsi, la différenciation ostéoclastique requiert deux voies de signalisation « immunologiques » : la voie RANK/RANKL (receptor activator of NF-κB ligand) et celle des protéines adaptatrices à domaine ITAM (immunoreceptor tyrosine based activation motif), DAP12 (DNAX-activating protein) et FcRγ (récepteur du fragment Fc des immunoglobulines). Mais la façon dont les deux voies s’associent pour induire le facteur de transcription clé de l’ostéoclastogenèse NFATc1 (nuclear factor of activated T-cells), restait à élucider. Une étude réalisée par le groupe de H. Takayanagi vient de permettre d’identifier les protéines tyrosine kinases Bruton et Tec, qui forment un complexe protéique capable d’intégrer ces deux voies de signalisation et, ainsi, permettent l’expression des gènes nécessaires à la différenciation ostéoclastique.