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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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The effect of OP on the actin cytoskeleton. Osteoclasts were fixed and stained with rhodamine-phalloidin. Actin filament organization in cells treated with PBS or OP is shown. Cells were examined by confocal microscopy. The actin staining of osteoclasts derived from wild-type (+/+) and  (−/−) mice are shown.
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Figure 2: The effect of OP on the actin cytoskeleton. Osteoclasts were fixed and stained with rhodamine-phalloidin. Actin filament organization in cells treated with PBS or OP is shown. Cells were examined by confocal microscopy. The actin staining of osteoclasts derived from wild-type (+/+) and (−/−) mice are shown.

Mentions: As shown in Fig. 1 (upper panels) and Fig. 2 (+/+ PBS), osteoclasts plated on glass coverslips arranged their actin cytoskeleton in peripheral rows of dot-like structures (podosomes). In some cells, podosomes were further organized into actin ring–like structures found in actively resorbing osteoclasts (Fig. 2, PBS +/+) (Taylor et al. 1989; Kanehisa et al. 1990; Lakkakorpi et al. 1993; for review see Horton et al. 1996). Podosomes were not observed in Gsn−/− osteoclasts (Fig. 1, lower panels). Instead, F-actin was present in a peripheral web-like structure, which was often bipartite (Fig. 2, lower panels) or present diffusely throughout the cell as seen in the higher magnification (Fig. 1, lower panels). The peripheral row of dot-like structures was never observed in Gsn−/− osteoclasts.


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)

The effect of OP on the actin cytoskeleton. Osteoclasts were fixed and stained with rhodamine-phalloidin. Actin filament organization in cells treated with PBS or OP is shown. Cells were examined by confocal microscopy. The actin staining of osteoclasts derived from wild-type (+/+) and  (−/−) mice are shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2169374&req=5

Figure 2: The effect of OP on the actin cytoskeleton. Osteoclasts were fixed and stained with rhodamine-phalloidin. Actin filament organization in cells treated with PBS or OP is shown. Cells were examined by confocal microscopy. The actin staining of osteoclasts derived from wild-type (+/+) and (−/−) mice are shown.
Mentions: As shown in Fig. 1 (upper panels) and Fig. 2 (+/+ PBS), osteoclasts plated on glass coverslips arranged their actin cytoskeleton in peripheral rows of dot-like structures (podosomes). In some cells, podosomes were further organized into actin ring–like structures found in actively resorbing osteoclasts (Fig. 2, PBS +/+) (Taylor et al. 1989; Kanehisa et al. 1990; Lakkakorpi et al. 1993; for review see Horton et al. 1996). Podosomes were not observed in Gsn−/− osteoclasts (Fig. 1, lower panels). Instead, F-actin was present in a peripheral web-like structure, which was often bipartite (Fig. 2, lower panels) or present diffusely throughout the cell as seen in the higher magnification (Fig. 1, lower panels). The peripheral row of dot-like structures was never observed in Gsn−/− osteoclasts.

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