Protein kinase C–delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts

Cremasco, Viviana; Decker, Corinne E.; Stumpo, Deborah J.; Blackshear, Perry J.; Nakayama, Keiichi I.; Nakayama, Keiko; Lupu, Traian S.; Graham, Daniel B.; Novack, Deborah V.; Faccio, Roberta

doi:10.1002/jbmr.1701

Cited by 50 publications

(51 citation statements)

References 43 publications

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“…8F) are also consistent with the fact that treatment of mice with enzastaurin, a PKCb inhibitor, can reduce osteoclastic bone destruction caused by metastatic breast cancer cells (Dudek et al 2008). Interestingly, Cremasco et al (2012) have shown that another PKC, PKCd, was also required for osteoclast function in vivo because it promotes cathepsin K exocytosis. Together, these and our findings suggest that multiple members of the PKC family might contribute nonredundantly to the resorptive function of osteoclasts.…”

Section: Lysosomal Biogenesis In Osteoclasts Genes and Development 965supporting

confidence: 76%

A RANKL–PKCβ–TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts

et al. 2013

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Bone resorption by osteoclasts requires a large number of lysosomes that release proteases in the resorption lacuna. Whether lysosomal biogenesis is a consequence of the action of transcriptional regulators of osteoclast differentiation or is under the control of a different and specific transcriptional pathway remains unknown. We show here, through cell-based assays and cell-specific gene deletion experiments in mice, that the osteoclast differentiation factor RANKL promotes lysosomal biogenesis once osteoclasts are differentiated through the selective activation of TFEB, a member of the MITF/TFE family of transcription factors. This occurs following PKCb phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor. Supporting these biochemical observations, mice lacking in osteoclasts-either TFEB or PKCb-show decreased lysosomal gene expression and increased bone mass. Altogether, these results uncover a RANKL-dependent signaling pathway taking place in differentiated osteoclasts and culminating in the activation of TFEB to enhance lysosomal biogenesis-a necessary step for proper bone resorption.[Keywords: osteoclast; RANKL; lysosomal biogenesis; TFEB; PKCb] Supplemental material is available for this article. Received January 11, 2013; revised version accepted March 21, 2013. Bone is constantly remodeled through the coordinated action of two cell types: the osteoblast and the osteoclast (Ducy et al. 2000;Teitelbaum 2000). While the osteoblast synthesizes and mineralizes the bone extracellular matrix (ECM), the osteoclast is responsible for resorbing this mineralized ECM. To achieve this specialized task, differentiated and multinucleated osteoclasts attach tightly to the bone surface and generate closed resorption lacunae. These resorption lacunae are characterized by an acidic pH (;4.5) and contain numerous proteases that are exported by the large number of lysosomes present in this cell type (Coxon and Taylor 2008). Proteases and acidification of the lacunae are both necessary for efficient bone resorption. The importance of lysosomal biogenesis for osteoclast function and optimum bone resorption underscores the need to elucidate how this aspect of osteoclast biology is regulated.Over the last two decades, our understanding of the mechanisms by which cells of the myeloid lineage differentiate into functional multinucleated osteoclasts has made considerable progress (Teitelbaum and Ross 2003;Takayanagi 2007). This led to the identification of two cytokines, RANKL and M-CSF (Yoshida et al. 1990;Lacey et al. 1998), as critical determinants of this process and the identification of numerous transcription factors acting downstream from these cytokines. Some of these factors-PU.1, c-FOS, JunB, Fra-1, NFkB, and PPARg-act early in the differentiation process within the myeloid precursor cells (Grigoriadis et al. 1994;Iotsova et al. 1997;Tondravi et al. 1997;Matsuo et al. 2000;Kenner et ...

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Section: Lysosomal Biogenesis In Osteoclasts Genes and Development 965supporting

confidence: 76%

A RANKL–PKCβ–TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts

et al. 2013

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“…In vitro experiments were repeated with bone marrow from both mice of C57BL/6-129 and C57BL/6 background. Analysis of bone phenotype by microCT and histology was performed as described (37). All experiments were approved by the Washington University School of Medicine animal care and use committee.…”

Section: Methodsmentioning

confidence: 99%

Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

Decker

Yang

Rimer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Phospholipase C gamma-2 (PLCγ2)-dependent calcium (Ca 2+ ) oscillations are indispensable for nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation and downstream gene transcription driving osteoclastogenesis during skeletal remodeling and pathological bone loss. Here we describe, to our knowledge, the first known function of transmembrane protein 178 (Tmem178), a PLCγ2 downstream target gene, as a critical modulator of the NFATc1 axis. In surprising contrast to the osteopetrotic phenotype of PLCγ2 −/− mice, Tmem178 −/− mice are osteopenic in basal conditions and are more susceptible to inflammatory bone loss, owing to enhanced osteoclast formation. Mechanistically, Tmem178 localizes to the ER membrane and regulates RANKL-induced Ca 2+ fluxes, thus controlling NFATc1 induction. Importantly, down-regulation of Tmem178 is observed in human CD14 + monocytes exposed to plasma from systemic juvenile idiopathic arthritis patients. Similar to the mouse model, reduced Tmem178 expression in human cells correlates with excessive osteoclastogenesis. In sum, these findings identify an essential role for Tmem178 to maintain skeletal mass and limit pathological bone loss.

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“…To determine whether ActA treatment decreased mature OCLmediated bone resorption, functional measurements of OCL activity were employed (Cremasco et al, 2012). First, mature OCLs were treated with combinations of RANKL and ActA in the presence of bovine bone powder.…”

Section: Activin a Suppresses Mature Osteoclastsmentioning

confidence: 99%

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

Fowler

Kamalakar

Akel

et al. 2015

Journal of Cell Science

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BSTRACTThe process of osteoclastic bone resorption is complex and regulated at multiple levels. The role of osteoclast (OCL) fusion and motility in bone resorption are unclear, with the movement of OCL on bone largely unexplored. RANKL (also known as TNFSF11) is a potent stimulator of murine osteoclastogenesis, and activin A (ActA) enhances that stimulation in whole bone marrow. ActA treatment does not induce osteoclastogenesis in stroma-free murine bone marrow macrophage cultures (BMM), but rather inhibits RANKL-induced osteoclastogenesis. We hypothesized that ActA and RANKL differentially regulate osteoclastogenesis by modulating OCL precursors and mature OCL migration. Time-lapse video microscopy measured ActA and RANKL effects on BMM and OCL motility and function. ActA completely inhibited RANKLstimulated OCL motility, differentiation and bone resorption, through a mechanism mediated by ActA-dependent changes in SMAD2, AKT1 and inhibitor of nuclear factor kB (IkB) signaling. The potent and dominant inhibitory effect of ActA was associated with decreased OCL lifespan because ActA significantly increased activated caspase-3 in mature OCL and OCL precursors.Collectively, these data demonstrate a dual action for ActA on murine OCLs.

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Protein kinase C–delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts

Cited by 50 publications

References 43 publications

A RANKL–PKCβ–TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts

A RANKL–PKCβ–TFEB signaling cascade is necessary for lysosomal biogenesis in osteoclasts

Tmem178 acts in a novel negative feedback loop targeting NFATc1 to regulate bone mass

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

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