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Gelsolin deficiency blocks podosome assembly and produces increased bone mass and strength.

Chellaiah M, Kizer N, Silva M, Alvarez U, Kwiatkowski D, Hruska KA - J. Cell Biol. (2000)

Bottom Line: They failed to respond to the autocrine factor, OP, with stimulation of motility and bone resorption.Gelsolin deficiency was associated with normal skeletal development and endochondral bone growth.These observations demonstrate the critical role of gelsolin in podosome assembly, rapid cell movements, and signal transduction through the alpha(v)beta(3) integrin.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Department of Medicine, Barnes-Jewish Hospital, Washington University, St. Louis, Missouri 63110, USA.

ABSTRACT
Osteoclasts are unique cells that utilize podosomes instead of focal adhesions for matrix attachment and cytoskeletal remodeling during motility. We have shown that osteopontin (OP) binding to the alpha(v)beta(3) integrin of osteoclast podosomes stimulated cytoskeletal reorganization and bone resorption by activating a heteromultimeric signaling complex that includes gelsolin, pp(60c-src), and phosphatidylinositol 3'-kinase. Here we demonstrate that gelsolin deficiency blocks podosome assembly and alpha(v)beta(3)-stimulated signaling related to motility in gelsolin- mice. Gelsolin-deficient osteoclasts were hypomotile due to retarded remodeling of the actin cytoskeleton. They failed to respond to the autocrine factor, OP, with stimulation of motility and bone resorption. Gelsolin deficiency was associated with normal skeletal development and endochondral bone growth. However, gelsolin- mice had mildly abnormal epiphyseal structure, retained cartilage proteoglycans in metaphyseal trabeculae, and increased trabecular thickness. With age, the gelsolin-deficient mice expressed increased trabecular and cortical bone thickness producing mechanically stronger bones. These observations demonstrate the critical role of gelsolin in podosome assembly, rapid cell movements, and signal transduction through the alpha(v)beta(3) integrin.

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Vinculin distribution in Gsn+/+ and Gsn−/− osteoclasts. In Gsn+/+ osteoclasts, vinculin was arrayed in often dual rows bordering actin rings shown here as the unstained ring between the vinculin (+/+). Two types of vinculin distribution were observed in the Gsn−/− osteoclasts: a peripheral distribution intermixed in the actin mesh (middle panels, +/+), or a diffuse distribution (lower panels, −/−).
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Figure 6: Vinculin distribution in Gsn+/+ and Gsn−/− osteoclasts. In Gsn+/+ osteoclasts, vinculin was arrayed in often dual rows bordering actin rings shown here as the unstained ring between the vinculin (+/+). Two types of vinculin distribution were observed in the Gsn−/− osteoclasts: a peripheral distribution intermixed in the actin mesh (middle panels, +/+), or a diffuse distribution (lower panels, −/−).

Mentions: Immunolocalization of vinculin was performed in Gsn+/+ and Gsn−/− osteoclasts to further define their adhesion structures. Vinculin is involved in assembling focal adhesion plaques and mediating anchorage to the cytoskeleton (Steimle et al. 1999). It has also been shown to have regulatory roles in adhesion, spreading, and motility of cells in culture (Xu et al. 1998; Rodriguez Fernandez et al. 1992, Rodriguez Fernandez et al. 1993). In the Gsn+/+ osteoclasts (Fig. 6, PBS +/+), vinculin was arrayed peripherally, forming a double band with areas of actin ring structure between the double band. These results are in agreement with prior studies in rat and avian osteoclasts (Taylor et al. 1989; Lakkakorpi et al. 1993). In areas of peripheral podosomes, vinculin was organized in a single intense band at the cell periphery and in the podosome structures. After OP treatment, changes in vinculin distribution (Fig. 6, OP +/+) lagged behind those of actin (Fig. 1), gelsolin (Fig. 3), and the αvβ3 integrin (data not shown), which were dramatically redistributed at 15 min. Vinculin was detected in the newly formed podosomes of the OP-treated Gsn+/+ osteoclasts, probably translocating from an intracellular pool different from the formed adhesion structures. In Gsn−/− osteoclasts, vinculin was also arrayed peripherally in discrete attachment sites with a unique structure not resembling podosomes or focal adhesions (Fig. 6, middle panels). In Gsn−/− osteoclasts with a diffuse actin distribution as in Fig. 1, vinculin was also arrayed diffusely with discrete attachment sites scattered throughout the cells (Fig. 6, lower panels).


Gelsolin deficiency blocks podosome assembly and produces increased bone mass and strength.

Chellaiah M, Kizer N, Silva M, Alvarez U, Kwiatkowski D, Hruska KA - J. Cell Biol. (2000)

Vinculin distribution in Gsn+/+ and Gsn−/− osteoclasts. In Gsn+/+ osteoclasts, vinculin was arrayed in often dual rows bordering actin rings shown here as the unstained ring between the vinculin (+/+). Two types of vinculin distribution were observed in the Gsn−/− osteoclasts: a peripheral distribution intermixed in the actin mesh (middle panels, +/+), or a diffuse distribution (lower panels, −/−).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2169374&req=5

Figure 6: Vinculin distribution in Gsn+/+ and Gsn−/− osteoclasts. In Gsn+/+ osteoclasts, vinculin was arrayed in often dual rows bordering actin rings shown here as the unstained ring between the vinculin (+/+). Two types of vinculin distribution were observed in the Gsn−/− osteoclasts: a peripheral distribution intermixed in the actin mesh (middle panels, +/+), or a diffuse distribution (lower panels, −/−).
Mentions: Immunolocalization of vinculin was performed in Gsn+/+ and Gsn−/− osteoclasts to further define their adhesion structures. Vinculin is involved in assembling focal adhesion plaques and mediating anchorage to the cytoskeleton (Steimle et al. 1999). It has also been shown to have regulatory roles in adhesion, spreading, and motility of cells in culture (Xu et al. 1998; Rodriguez Fernandez et al. 1992, Rodriguez Fernandez et al. 1993). In the Gsn+/+ osteoclasts (Fig. 6, PBS +/+), vinculin was arrayed peripherally, forming a double band with areas of actin ring structure between the double band. These results are in agreement with prior studies in rat and avian osteoclasts (Taylor et al. 1989; Lakkakorpi et al. 1993). In areas of peripheral podosomes, vinculin was organized in a single intense band at the cell periphery and in the podosome structures. After OP treatment, changes in vinculin distribution (Fig. 6, OP +/+) lagged behind those of actin (Fig. 1), gelsolin (Fig. 3), and the αvβ3 integrin (data not shown), which were dramatically redistributed at 15 min. Vinculin was detected in the newly formed podosomes of the OP-treated Gsn+/+ osteoclasts, probably translocating from an intracellular pool different from the formed adhesion structures. In Gsn−/− osteoclasts, vinculin was also arrayed peripherally in discrete attachment sites with a unique structure not resembling podosomes or focal adhesions (Fig. 6, middle panels). In Gsn−/− osteoclasts with a diffuse actin distribution as in Fig. 1, vinculin was also arrayed diffusely with discrete attachment sites scattered throughout the cells (Fig. 6, lower panels).

Bottom Line: They failed to respond to the autocrine factor, OP, with stimulation of motility and bone resorption.Gelsolin deficiency was associated with normal skeletal development and endochondral bone growth.These observations demonstrate the critical role of gelsolin in podosome assembly, rapid cell movements, and signal transduction through the alpha(v)beta(3) integrin.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Department of Medicine, Barnes-Jewish Hospital, Washington University, St. Louis, Missouri 63110, USA.

ABSTRACT
Osteoclasts are unique cells that utilize podosomes instead of focal adhesions for matrix attachment and cytoskeletal remodeling during motility. We have shown that osteopontin (OP) binding to the alpha(v)beta(3) integrin of osteoclast podosomes stimulated cytoskeletal reorganization and bone resorption by activating a heteromultimeric signaling complex that includes gelsolin, pp(60c-src), and phosphatidylinositol 3'-kinase. Here we demonstrate that gelsolin deficiency blocks podosome assembly and alpha(v)beta(3)-stimulated signaling related to motility in gelsolin- mice. Gelsolin-deficient osteoclasts were hypomotile due to retarded remodeling of the actin cytoskeleton. They failed to respond to the autocrine factor, OP, with stimulation of motility and bone resorption. Gelsolin deficiency was associated with normal skeletal development and endochondral bone growth. However, gelsolin- mice had mildly abnormal epiphyseal structure, retained cartilage proteoglycans in metaphyseal trabeculae, and increased trabecular thickness. With age, the gelsolin-deficient mice expressed increased trabecular and cortical bone thickness producing mechanically stronger bones. These observations demonstrate the critical role of gelsolin in podosome assembly, rapid cell movements, and signal transduction through the alpha(v)beta(3) integrin.

Show MeSH
Related in: MedlinePlus