Osteoclast Ruffled Border Has Distinct Subdomains for Secretion and Degraded Matrix Uptake

Mulari, Mika; Zhao, Haibo; Lakkakorpi, Päivi T.; Väänänen, H. Kalervo

doi:10.1034/j.1600-0854.2003.40206.x

Cited by 120 publications

(128 citation statements)

References 63 publications

Supporting

Mentioning

116

Contrasting

Order By: Relevance

“…After attachment to bone, the ruffled border secretes enzymes and protons enabling the solubilization and digestion of the bone matrix. Rapid cytoskeletal reorganization is essential for osteoclast function and formation of the specialized membranes (21,35). NMP treatment disrupted actin ring formation in osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

Ghayor

Correro

Lange

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Regulation of RANKL (receptor activator of nuclear factor B ligand)-induced osteoclast differentiation is of current interest in the development of antiresorptive agents. Osteoclasts are multinucleated cells that play a crucial role in bone resorption. In this study, we investigated the effects of N-methylpyrrolidone (NMP) on the regulation of RANKL-induced osteoclastogenesis. NMP inhibited RANKL-induced tartrate-resistant acid phosphatase activity and the formation of tartrate-resistant acid phosphatase-positive multinucleated cells. The RANKL-induced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) and c-Fos, which are key transcription factors for osteoclastogenesis, was also reduced by treatment with NMP. Furthermore, NMP induced disruption of the actin rings and decreased the mRNAs of cathepsin K and MMP-9 (matrix metalloproteinase-9), both involved in bone resorption. Taken together, these results suggest that NMP inhibits osteoclast differentiation and attenuates bone resorption. Therefore, NMP could prove useful for the treatment of osteoporosis or other bone diseases associated with excessive bone resorption.Bone remodeling is a physiological process that involves the resorption and synthesis of bone by osteoclasts and osteoblasts, respectively (1, 2). Osteoclasts are known to be formed by the fusion of hematopoietic cells of the monocyte-macrophage lineage during the early stage of the differentiation process (3). This process consists of multiple steps, including differentiation of osteoclast precursors into mononuclear osteoclasts, fusion of mononuclear preosteoclasts into mature multinucleated osteoclasts, and activation of osteoclasts to resorb bone (4 -7). The terminal differentiation in this lineage is characterized by acquisition of mature phenotypic markers such as expression of tartrate-resistant acid phosphatase (TRAP), 2 the calcitonin receptor, MMP-9, and cathepsin K, as well as morphological conversion into large multinucleated cells and the ability to form resorption lacunae on bone (8 -10). The essential signaling molecules for osteoclast differentiation include RANKL and M-CSF (macrophage colony-stimulating factor) in bone marrow-derived macrophage precursor cells (11,12).RANKL is a member of the TNF superfamily that is expressed in osteoblasts. It interacts with the osteoclast cell surface receptor RANK, which in turn recruits TNF receptor-associated factors and plays a crucial role in the osteoclast differentiation axis (13,14). The downstream intracellular signaling mediated by RANK in osteoclast progenitor cells includes TRAF6 (TNF receptor-associated factor 6)-dependent activation of NF-B via the IB kinase complex and MAPKs such as ERK, p38 MAPK, and JNK (7,11,15). In addition, RANKL induces the key transcription factors for osteoclastogenesis, NFATc1 and c-Fos (9, 16, 17). Therefore, chemical or natural compounds that specifically inhibit these steps could be developed as antiresorptive drugs for the treatment of metabolic bone disorders characterized by e...

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

Ghayor

Correro

Lange

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Depending on the cell type and labelling conditions, a proportion (up to 25%) of the transferrin has a half-life of only 5-7 minutes inside the cell, whereas a larger proportion accumulates in the recycling endosome and it can take more than 60 minutes before these molecules are recycled back to the plasma membrane (Hopkins et al, 1994). In osteoclasts, it has been shown that endocytosed transferrin reaches the ruffled border after 30 minutes of incubation (Mulari et al, 2003;Palokangas et al, 1997), establishing that there is cross-talk between the recycling and late endosome/ ruffled border. However, the amount of transferrin that reaches the ruffled border has not been established.…”

Section: Co-localization Of Dextran With Endocytic Markersmentioning

confidence: 99%

“…This dynamic equilibrium is supported by the finding that basolaterally endocytosed transferrin is found in the area of the ruffled border after 30 minutes of chase (Palokangas et al, 1997). It was also recently suggested that the ruffled border is divided into a peripheral secretory subdomain and a centrally located uptake zone (Mulari et al, 2003). Studies with differentially targeted virus particles, in conjunction with the localization of lysosomeassociated membrane proteins (LAMPs) and the small GTPase Rab7 to this plasma-membrane domain, also indicate a high similarity of the ruffled border to the late-endosome/lysosome compartment (Palokangas et al, 1997;Salo et al, 1996).…”

mentioning

confidence: 99%

“…Actin filaments have been linked to endocytosis from the apical plasma membrane in several polarized cell types (Apodaca, 2001) and the actin-disrupting drug cytochalasin has been shown to slow basolateral to apical transcytosis significantly (Maples et al, 1997). In osteoclasts, both microtubules and F-actin are found in the central part of the ruffled border, which is surrounded by the actin ring of the sealing zone (Mulari et al, 2003). The rearrangement of the actin cytoskeleton at the beginning of the resorption cycle is stimulated by engagement of the major osteoclast integrin αvβ3, which activates a heteromultimeric signalling complex that includes actin-binding proteins, the tyrosine kinase pp(60c-src) and the lipid phosphatidylinositol-3-kinase (PI-3-kinase) (Hruska et al, 1995).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Endocytic trafficking in actively resorbing osteoclasts

Stenbeck

Horton

2004

Journal of Cell Science

View full text Add to dashboard Cite

Endocytosis and the subsequent intracellular trafficking of the endocytosed material are important determinants of cellular function. Osteoclasts, cells of the monocyte/macrophage family, are specialized for the internalization and processing of bone matrix. Transcytosis of endocytosed material has been observed in osteoclasts but the precise mechanism controlling this process is unclear. Here, we investigate the regulation of these trafficking events. To establish the directionality and kinetics of trafficking events in resorbing osteoclasts, we devised a system using fluorescent low-molecular-weight markers as probes to follow the route taken by the digested bone matrix. We demonstrate that this route is largely distinct from the pathway followed by proteins taken up by receptor-mediated endocytosis at the basolateral plasma membrane. Endocytosis and transcytosis from the ruffled border are fast processes, with a half-life of the endocytosed material inside the cells of 22 minutes. We demonstrate the crucial role of the microtubule network in transport from the ruffled-border area and provide evidence for a role of the cytoskeleton in the overall efficacy of trafficking. Moreover, we analyse the effect of the V-ATPase inhibitor bafilomycin A1 on endocytic uptake, which gives insight into the pH-dependent regulation of membrane trafficking and resorption in osteoclasts.

show abstract

“…Once the mineral degradation is underway, the degradation of bone organic matrix (mostly type 1 collagen) can take place. This function is performed by many degradative factors including acid phosphatases (TRAP), matrix metalloproteinases (MMPs) and the lysosomal enzyme cathepsin K, which, like the ion channels necessary for acidification, polarize to the ruffled membrane after osteoclast attachment to the bone, to be as close as possible to the site of action (Mulari et al, 2003) ( Figure 5). …”

Section: Osteoclastic Bone Resorptionmentioning

confidence: 99%

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

et al. 2011

View full text Add to dashboard Cite

Osteoclast Ruffled Border Has Distinct Subdomains for Secretion and Degraded Matrix Uptake

Cited by 120 publications

References 63 publications

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

Inhibition of Osteoclast Differentiation and Bone Resorption by N-Methylpyrrolidone

Endocytic trafficking in actively resorbing osteoclasts

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

Contact Info

Product

Resources

About