Recent advances in understanding the mechanisms of osteoclast precursor fusion

Oursler, Merry Jo

doi:10.1002/jcb.22640

Cited by 48 publications

(50 citation statements)

References 51 publications

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“…Many surface receptors including DC-STAMP and MFR/SIRPα, are critical for fusion from mononucleated precursors into multinucleated cells. In addition, ADAM8 and ADAM12 which are disintegrins/metalloproteinases secreted prior to fusion, may be affected in this model (Oursler, 2010). Calcitonin, the ligand for CTR, is responsible for lowering calcium levels in the blood by inhibiting bone resorption by inducing morphological changes leading to osteoclast retraction (Naot and Cornish, 2008).…”

Section: Discussionmentioning

confidence: 99%

Augmented LPS responsiveness in type 1 diabetes‐derived osteoclasts

Catalfamo

Calderon

Harden

et al. 2012

Journal Cellular Physiology

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Bone abnormalities are frequent co-morbidities of type 1 diabetes [T1D] and are principally mediated by osteoblasts and osteoclasts which in turn are regulated by immunologic mediators. While decreased skeletal health in T1D involves alterations in osteoblast maturation and function, the affect of altered immune function on osteoclasts in T1D-associated bone and joint pathologies is less understood. Here T1D-associated osteoclast-specific differentiation and function in the presence and absence of inflammatory mediators was characterized utilizing bone marrow-derived osteoclasts [BM-OCs] isolated from non-obese diabetic [NOD] mice, a model for spontaneous autoimmune diabetes with pathology similar to individuals with T1D. Differentiation and osteoclast-mediated bone resorption were evaluated along with cathepsin K, MMP-9, and immune soluble mediator expression. The affect of LPS, a pro-inflammatory cytokine cocktail, and NOD-derived conditioned supernatants on BM-OC function was also determined. Although NOD BM-OCs cultures contained smaller osteoclasts, they resorbed more bone concomitant with increased cathepsin K, MMP-9 and pro-osteoclastogenic mediator expression. NOD BM-OCs also displayed an inhibition of LPS-induced deactivation that was not a result of soluble mediators produced by NOD BM-OCs, although a pro-inflammatory milieu did enhance NOD BM-OCs bone resorption. Together these data indicate that osteoclasts from a T1D mouse model hyper-respond to RANK-L resulting in excessive bone degradation via enhanced cathepsin K and MMP-9 secretion concomitant with an increased expression of pro-osteoclastic soluble mediators. Our data also suggest that inhibition of LPS-induced deactivation in NOD-derived BM-OC cultures is most likely due to NOD osteoclast responsiveness rather than LPS-induced expression of soluble mediators.

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Section: Discussionmentioning

confidence: 99%

Augmented LPS responsiveness in type 1 diabetes‐derived osteoclasts

Catalfamo

Calderon

Harden

et al. 2012

Journal Cellular Physiology

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“…Indeed, osteoclast precursor motility is required for cell-cell interaction, leading to subsequent differentiation and fusion (Fujita et al, 2012;Oursler, 2010). We therefore investigated whether ActA altered pre-osteoclast motility using time-lapse video microscopy of OCL precursors plated on both plastic and bovine bone.…”

Section: Activin a Decreases The Motility Of Mbmm Precursorsmentioning

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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“…18,19) Of the multiple candidate factors, we next focused on DC-STAMP and ATP6v0d2 because both factors have been reported to be involved in osteoclast fusion 16) and are downstream of NFATc1, a master transcription factor for osteoclastogenesis. 20) Using RT-PCR, we found that the levels of NFATc1, TRAP, and DC-STAMP expression in RAW-ISG cells in response to RANKL treatment were somewhat higher than those in RAWMock cells under the same conditions (Fig.…”

Section: Isg15 Suppresses Atp6v0d2mentioning

confidence: 99%

ISG15 Regulates RANKL-Induced Osteoclastogenic Differentiation of RAW264 Cells

Takeuchi

Shimakawa

Tamura

et al. 2015

Biological & Pharmaceutical Bulletin

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Interferon-stimulated gene 15 kDa (ISG15) is a protein upregulated by interferon-β that negatively regulates osteoclastogenesis. We investigated the role of ISG15 in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenic differentiation of murine RAW264 cells. RANKL stimulation induced ISG15 expression in RAW264 cells at both the mRNA and protein levels. Overexpression of ISG15 in RAW264 cells resulted in suppression of cell fusion in RANKL-stimulated cells as well as the reduced expression of ATP6v0d2, a gene essential for cell fusion in osteoclastogenic differentiation. These results suggest that ISG15 suppresses RANKL-induced osteoclastogenesis, at least in part, through inhibition of ATP6v0d2 expression.Key words interferon-stimulated gene 15 kDa (ISG15); osteoclast; interferon; receptor activator of nuclear factor-κB ligand (RANKL); RAW264; ATP6v0d2Interferon-α/β is a multifunctional cytokine that exerts various biological functions in immunity, cell differentiation, and so on via the induction of downstream genes called interferonstimulated genes (ISGs).1,2) Interferon-stimulated gene 15 kDa (ISG15), a ubiquitin-like protein, is one of the proteins that are most upregulated by interferon stimulation.3,4) Upon stimulation of the cells with interferon or pathogenic materials such as lipopolysaccharides, the expression of ISG15 and several other enzymes that catalyze protein modification with ISG15 (ISGylation) is induced, followed by the ISGylation of various cellular proteins. ISGylation affects the nuclear factor-kappa B (NF-κB) signaling pathway as well as the activity of doublestranded RNA-activated protein kinase, 5,6) both of which have important roles in osteoclastogenic differentiation. 7,8) Osteoclasts are tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells derived from monocyte/macrophage lineage cells. 7,9) Receptor activator of nuclear factor-κB ligand (RANKL) is essential for the induction of osteoclastogenesis.10) The murine RAW264 cell line is a useful model of osteoclastogenesis as, upon stimulation with RANKL, RAW264 cells differentiate into TRAP-positive mononuclear cells, which subsequently undergo cell fusion to form TRAPpositive multinuclear osteoclasts. In vivo, osteoclastogenesis is tightly controlled by factors produced from cells such as osteoblasts and osteocytes, and deregulation of osteoclastogenesis results in various diseases such as osteoporosis. 7,9,11,12)

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Recent advances in understanding the mechanisms of osteoclast precursor fusion

Cited by 48 publications

References 51 publications

Augmented LPS responsiveness in type 1 diabetes‐derived osteoclasts

Augmented LPS responsiveness in type 1 diabetes‐derived osteoclasts

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

ISG15 Regulates RANKL-Induced Osteoclastogenic Differentiation of RAW264 Cells

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