Hck contributes to bone homeostasis by controlling the recruitment of osteoclast precursors

ABSTRACT In osteoclasts, Src controls podosome organization and bone degradation, which leads to an osteopetrotic phenotype in src ؊/؊ mice. Since this phenotype was even more severe in src ؊/؊ hck ؊/؊ mice, we examined the individual contribution of Hck in bone homeostasis. Compared to wt mice, hck ؊/؊ mice exhibited an osteopetrotic phenotype characterized by an increased density of trabecular bone and decreased bone degradation, although osteoclastogenesis was not impaired. Podosome organization and matrix degradation were found to be defective in hck ؊/؊ osteoclast precursors (preosteoclast) but were normal in mature hck ؊/؊ osteoclasts, probably through compensation by Src, which was specifically overexpressed in mature osteoclasts. As a consequence of podosome defects, the 3-dimensional migration of hck ؊/؊ preosteoclasts was strongly affected in vitro. In vivo, this translated by altered bone homing of preosteoclasts in hck ؊/؊ mice: in metatarsals of 1-wk-old mice, when bone formation strongly depends on the recruitment of these cells, reduced numbers of osteoclasts and abnormal developing trabecular bone were observed. This phenotype was still detectable in adults. In summmary, Hck is one of the very few effectors of preosteoclast recruitment described to date and thereby plays a critical role in bone remodeling.-Vérollet, C., Gallois, A., Dacquin, R., Lastrucci, C., Pandruvada, S. M. N., Ortega, N., Poincloux, R., Behar, A., Cougoule, C., Lowell, C., Al Saati, T., Jurdic, P., Maridonneau-Parini, I. Hck contributes to bone homeostasis by controlling the recruitment of osteoclast precursors. FASEB J. 27, 3608 -3618 (2013). www.fasebj.org Key Words: osteopetrosis ⅐ cell migration ⅐ podosomes ⅐ Src tyrosine kinases Bone is renewed continuously by a process known as bone remodeling. Bone remodeling is accomplished by 3 cell types: osteocytes, osteoblasts, and osteoclasts (OCs). Osteocytes are the mechanical sensors of bone that regulate osteoclast formation. Osteoblasts synthetize the matrix and promote its mineralization, while OCs are responsible for degradation of bones during bone development, homeostasis, and repair. The formation and degradation of bone are tightly balanced in both time and space. A dysregulation of this tight balance between bone formation and bone degradation may result either in loss of bone mass, such as in osteoporosis, or in contrast, in a progressive increase in bone mass, such as in osteopetrosis. Degrading OCs are large multinucleated giant cells formed by the differentiation and fusion of mononuclear monocyte lineage precursors after stimulation by receptor activator of nuclear factor -B ligand (RANKL) and macrophage colony-stimulationg factor (M-CSF) (1-3). They are characterized by high levels of cathepsin K and tartrate resistant acidic phosphatase (TRAP) activities, whic

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16(+) monocyte population via the IL-10/STAT3 axis

The human CD14+ monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16+ monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by theCD16+CD163+MerTK+pSTAT3+ phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16+CD163+MerTK+pSTAT3+ cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16+CD163+MerTK+pSTAT3+ monocyte-to-macrophage differentiation program and its potential as a target for TB therapy,and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoringof treatment efficacy.Fil: Lastrucci, Claire. Centre National de la Recherche Scientifique; FranciaFil: Bénard, Alan. Centre National de la Recherche Scientifique; FranciaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pingris, Karine. Centre National de la Recherche Scientifique; FranciaFil: Souriant, Shanti. Centre National de la Recherche Scientifique; FranciaFil: Poincloux, Renaud. Centre National de la Recherche Scientifique; FranciaFil: Al Saati, Talal. Inserm; FranciaFil: Rasolofo, Voahangy. Pasteur Institute in Antananarivo; MadagascarFil: González Montaner, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Inwentarz, Sandra. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Moraña, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Kondova, Ivanela. Biomedical Primate Research Centre; Países BajosFil: Verreck, Franck A. W.. Biomedical Primate Research Centre; Países BajosFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Neyrolles, Olivier. Centre National de la Recherche Scientifique; FranciaFil: Maridonneau Parini, Isabel. Centre National de la Recherche Scientifique; FranciaFil: Lugo Villarino, Geanncarlo. Centre National de la Recherche Scientifique; FranciaFil: Cougoule, Celine. Centre National de la Recherche Scientifique; Franci

Les radicaux libres oxygenes : effets cellulaires et mecanismes de generation par la NADPH oxydase

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Etude moléculaire et cellulaire des fonctions associées à chacune des isoformes de la protéine tyrosine kinase Hck dans les phagocytes

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Etude du rôle de la protéine Hck, tyrosine kinase de la famille Src, dans la motilité des lysosomes (implication de la polymérisation de l'actine)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Etude des mécanismes contrôlant la sécrétion régulée des lysosomes dans les phagocytes (rôle de la tyrosine kinase de la famille Src, Hck)

TOULOUSE3-BU Sciences (315552104) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Etude de la régulation des fonctions bactéricides des macrophages par les mycobactéries

Les mycobactéries pathogènes sont capables de survivre et de se multiplier à l'intérieur des macrophages en régulant leurs réponses bactéricides. Ceci implique que les mycobactéries aient développé des mécanismes de résistance. Dans les macrophages " au repos ", les mycobactéries survivent à des temps précoces d'infection et ceci est régulé par un événement récepteur-dépendant. Les mycobactéries empruntent des récepteurs de phagocytose non opsoniques qui ne déclenchent pas des réponses bactéricides. Le CR3 est une nouvelle voie d'entrée non opsonique des mycobactéries sous réserve de son activation. C'est une voie d'entrée silencieuse. A des étapes tardives d'infection, seules les mycobactéries pathogènes comme M. tuberculosis sont capables de survivre. Cela nécessite la mise en place de facteurs de virulence. La protéine tyrosine phosphatase MptpA de M. tuberculosis est capable d'inhiber la phagocytose de mycobactéries pathogènes et non pathogènes.Pathogenic mycobacteria can survive and multiply into macrophages by regulating bactericidal responses. It implies that mycobacteria developped resistance mecanisms. In resting macrophages, mycobacteria survive at early time of infection and that is regulated by receptor-dependent event. Mycobacteria use non-opsonic phagocytosis receptors that are uncoupled from bactericidal responses. CR3 participates in the non-opsonic uptake of mycobacteria and depend on the state of receptor activation. CR3 is a new safe portal of entry. At late time of infection, pathogenic mycobacteria like M. tuberculosis survive in macrophages. This implies synthesis of virulence factors. The tyrosine phosphatase MptpA of M. tuberculosis inhibits phagocytosis of pathogenic and non pathogenic mycobacteria.TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Identification des composés de la surface des mycobactéries impliqués dans leur reconnaissance et leur internalisation par les macrophages humains (outils pour une nouvelle approche pharmacologique des infections microbactériennes)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

The osteoclast, a target cell for microorganisms

International audienceBone is a highly adaptive tissue with regenerative properties that is subject to numerous diseases. Infection is one of the causes of altered bone homeostasis. Bone infection happens subsequently to bone surgery or to systemic spreading of microorganisms. In addition to osteoblasts, osteoclasts (OCs) also constitute cell targets for pathogens. OCs are multinucleated cells that have the exclusive ability to resorb bone mineral tissue. However, the OC is much more than a bone eater. Beyond its role in the control of bone turnover, the OC is an immune cell that produces and senses inflammatory cytokines, ingests microorganisms and presents antigens. Today, increasing evidence shows that several pathogens use OC as a host cell to grow, generating debilitating bone defects. In this review, we exhaustively inventory the bacteria and viruses that infect OC and report the present knowledge in this topic. We point out that most of the microorganisms enhance the bone resorption activity of OC. We notice that pathogen interactions with the OC require further investigation, in particular to validate the OC as a host cell in vivo and to identify the cellular mechanisms involved in altered bone resorption. Thus, we conclude that the OC is a new cell target for pathogens; this new research area paves the way for new therapeutic strategies in the infections causing bone defects