Dramatic inhibition of osteoclast sealing ring formation and bone resorption in vitro by a WASP-peptide containing pTyr294 amino acid

Ma, Tao; Samanna, Venkatesababa; Chellaiah, Meenakshi A.

doi:10.1186/1750-2187-3-4

Cited by 17 publications

(20 citation statements)

References 36 publications

(72 reference statements)

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“…Podosomes were observed in cells plated on glass coverslips. Either actin aggregates or sealing rings were found in osteoclast cultures on apatite crystals (53), dentine (10,11), or human bone sections (data not shown). Formation of an actin-rich sealing ring may depend on minerals present in the bone.…”

Section: Discussionmentioning

confidence: 94%

“…dentine, ivory, and natural bone). We have used previously (1,10,11) and at this time biologically derived hard tissues, such as devitalized native bone or dentine slices, as substrates for in vitro bone resorption assays. Researchers also use osteologic discs containing submicron calcium phosphate films (ϳ0.6 m) on transparent quartz material (BD Biosciences) for in vitro bone resorption assays.…”

Section: Analysis Of Protein Profile In Osteoclasts Incubated With DImentioning

confidence: 99%

“…Furthermore, WASP integrates signals from Rho, Cdc42, and kinases to bind and stimulate actin polymerization and sealing ring formation in osteoclasts (5,7,10). Experiments with WASP peptides containing Pro-rich and Tyr(P) 294 -containing peptides demonstrated significant effects on osteoclast signaling and sealing ring formation (11). Modulation of the phosphorylation state of WASP by kinase(s) assists in integrating multiple signaling molecules that play a part in the assembly of * This work was supported, in whole or in part, by National Institutes of the sealing ring.…”

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confidence: 99%

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Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Sadashivaiah

Chellaiah

2010

Journal of Biological Chemistry

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The aim of this study is to identify the exact mechanism(s) by which cytoskeletal structures are modulated during bone resorption. In this study, we have shown the possible role of different actin-binding and signaling proteins in the regulation of sealing ring formation. Our analyses have demonstrated a significant increase in cortactin and a corresponding decrease in L-plastin protein levels in osteoclasts subjected to bone resorption for 18 h in the presence of RANKL, M-CSF, and native bone particles. Time-dependent changes in the localization of L-plastin (in actin aggregates) and cortactin (in the sealing ring) suggest that these proteins may be involved in the initial and maturation phases of sealing ring formation, respectively. siRNA to cortactin inhibits this maturation process but not the formation of actin aggregates. Osteoclasts treated as above but with TNF-␣ demonstrated very similar effects as observed with RANKL. Osteoclasts treated with a neutralizing antibody to TNF-␣ displayed podosome-like structures in the entire subsurface and at the periphery of osteoclast. It is possible that TNF-␣ and RANKL-mediated signaling may play a role in the early phase of sealing ring configuration (i.e. either in the disassembly of podosomes or formation of actin aggregates). Furthermore, osteoclasts treated with alendronate or ␣v reduced the formation of the sealing ring but not actin aggregates. The present study demonstrates a novel mechanistic link between L-plastin and cortactin in sealing ring formation. These results suggest that actin aggregates formed by L-plastin independent of integrin signaling function as a core in assembling signaling molecules (integrin ␣v␤3, Src, cortactin, etc.) involved in the maturation process.Osteoclasts, the multinucleated and terminally differentiated giant cells, are involved in bone resorption. The adhesion of osteoclasts to the bone during bone resorption leads to the formation of the clear zone, an actin-rich ring-like adhesion zone circumscribing an area of bone resorption. Formation of a clear zone or sealing zone (also known as the sealing ring) has been considered to be a marker of osteoclast activation and is fundamental to the process of osteoclast bone resorption. Sealing ring formation is mediated by the dynamics of the actin cytoskeleton. Distinct pathways and signaling molecules have been shown to play roles in the organization of the sealing ring during bone resorption. Our previous observations in gelsolin null (Gsn Ϫ/Ϫ ) 2 osteoclasts demonstrated that deficiency of this protein blocks podosome assembly and motility. However, the cells still exhibit sealing ring and matrix resorption (1). Therefore, Gsn Ϫ/Ϫ osteoclasts are capable of resorbing bone, but the resorbed areas are small due to the absence of podosomes and the resulting hypomotile nature of osteoclasts (1). Observations in Gsn Ϫ/Ϫ osteoclasts also suggest that the organization of the sealing ring presumably reflect changes in the role of actinbinding proteins. Spatial configurations of actin fil...

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Section: Discussionmentioning

confidence: 94%

Section: Analysis Of Protein Profile In Osteoclasts Incubated With DImentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Sadashivaiah

Chellaiah

2010

Journal of Biological Chemistry

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“…75 Activated WASP conformation enables access of Tyr291 (human)/Tyr294 (mouse) to modifying enzymes, 76,77 increasing WASP affinity to Arp2/3 complex and ultimately leading to sealing zone formation and bone resorption. 52,78 Surprisingly, WASP-null osteoclasts retain the capacity to polymerize actin but fail to assemble podosomes replaced by large actin-rich plaques. 79 Even if Cdc42 has been shown to be an important regulator of (N)-WASP, 80,81 notably because it is necessary for an efficient phosphorylation of Tyr291/Tyr294, 77 microinjection of activated Cdc42 alone is not sufficient to form a podosome belt in osteoclasts.…”

Section: Adhesion Structuresmentioning

confidence: 99%

Modulation of osteoclast differentiation and bone resorption by Rho GTPases

2014

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“…WASP integrates signals from Rho, Cdc42, and kinases that bind to the Arp2/3 complex and stimulates Arp2/3-dependent actin polymerization. Phosphorylation of WASP at tyr 291 , which is mediated by c-Src PTK in osteoclasts [106], is essential for osteoclast resorption in vitro [107] and increases the actin polymerization activity through the Arp2/3 complex [108,109]. The PY291 of WASP is a substrate of PTP-PEST, and the interaction among PTP-PEST, PSTPIP, and WASP allows PTP-PEST to dephosphorylate WASP [103].…”

Section: Ptp-pestmentioning

confidence: 99%

Role of protein-tyrosine phosphatases in regulation of osteoclastic activity

Sheng

Lau

2009

Cell. Mol. Life Sci.

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Osteoclasts, the primary cell type mediating bone resorption, are multinucleated, giant cells derived from hematopoietic cells of monocyte-macrophage lineage. Osteoclast activity is, in a large part, regulated by protein-tyrosine phosphorylation. While information about functional roles of several protein-tyrosine kinases (PTK), including c-Src, in osteoclastic resorption has been accumulated, little is known about the roles of protein-tyrosine phosphatases (PTPs) in regulation of osteoclast activity. Recent evidence implicates important regulatory roles for four PTPs (SHP-1, cyt-PTP-ε, PTP-PEST, and PTP-oc) in osteoclasts. Cyt-PTP-ε, PTP-PEST, and PTP-oc are positive regulators of osteoclast activity, while SHP-1 is a negative regulator. Of these PTPs in osteoclasts, only PTPoc is a positive regulator of c-Src PTK through dephosphorylation of the inhibitory phosphotyrosine-527 residue. Although some information about mechanisms of action of these PTPs to regulate osteoclast activity is reviewed in this article, much additional work is required to provide more comprehensive details about their functions in osteoclasts. KeywordsProtein-tyrosine dephosphorylation; Osteoclast; c-Src; Bone resorption; Protein-tyrosine phosphatases; PTP-oc; cytosolic PTP-ε; PTP-PEST; SHP-1 Bone and bone remodelingBone is a vital, dynamic connective tissue, comprising of a complex mixture of organic and inorganic materials. The large majority of the organic matter is type I collagen that is the basic building block of the bone matrix fiber network. The inorganic matter is composed primarily of calcium phosphate in the form of hydroxyapatite crystals. The cellular component of the bone is made up of three functionally distinct cell types: the first cell type is the osteoblast, which is derived from osteoprogenitor cells of the mesenchymal lineage [1]. Osteoblasts are the principal cell type that mediates bone formation by synthesizing bone matrix and by promoting mineralization of the newly synthesized matrix [1]. The second cell type is the osteocyte, which is the star-shaped, terminally differentiated osteoblast that is fully entrapped by the bone matrix [2]. Osteocytes are well situated within bone matrix to detect mechanical loading stress [3], have the ability to communicate with other bone cells through an extensive

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Dramatic inhibition of osteoclast sealing ring formation and bone resorption in vitro by a WASP-peptide containing pTyr294 amino acid

Cited by 17 publications

References 36 publications

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Modulation of osteoclast differentiation and bone resorption by Rho GTPases

Role of protein-tyrosine phosphatases in regulation of osteoclastic activity

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