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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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Mechanical strength of femurs from Gsn+/+ and Gsn−/− mice. (a) Graphic representation of the data generated by four-point bending test. The slope of the line relating bending and displacement is a reflection of stiffness or rigidity, and the area under the curve is the energy required to produce failure. (b) The ultimate moment-displacement curves for +/+ and −/− femurs. The normalized displacement at failure (ultimate) was greater in the Gsn−/− femurs (see Table ). (c) The energy required to produce failure was greater in the femurs from Gsn−/− mice (see Table ).
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Figure 11: Mechanical strength of femurs from Gsn+/+ and Gsn−/− mice. (a) Graphic representation of the data generated by four-point bending test. The slope of the line relating bending and displacement is a reflection of stiffness or rigidity, and the area under the curve is the energy required to produce failure. (b) The ultimate moment-displacement curves for +/+ and −/− femurs. The normalized displacement at failure (ultimate) was greater in the Gsn−/− femurs (see Table ). (c) The energy required to produce failure was greater in the femurs from Gsn−/− mice (see Table ).

Mentions: The imbalance between bone resorption and formation and the increased mineralization reported here may have affected bone strength, and the ability of the skeleton to resist damage (fracture) may be altered. To test this possibility, we performed four-point bending tests of mouse bones to assess their mechanical strength, as described in Materials and Methods. As shown in Fig. 11 and Table , the Gsn−/− bones required greater energy and greater maximal displacement to produce femoral failure compared with the Gsn+/+ femurs. Changes in bone stiffness resulting from over mineralization and decreased remodeling seen in some osteopetroses were not observed in the bones from the Gsn−/− mice.


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)

Mechanical strength of femurs from Gsn+/+ and Gsn−/− mice. (a) Graphic representation of the data generated by four-point bending test. The slope of the line relating bending and displacement is a reflection of stiffness or rigidity, and the area under the curve is the energy required to produce failure. (b) The ultimate moment-displacement curves for +/+ and −/− femurs. The normalized displacement at failure (ultimate) was greater in the Gsn−/− femurs (see Table ). (c) The energy required to produce failure was greater in the femurs from Gsn−/− mice (see Table ).
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Related In: Results  -  Collection

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

Figure 11: Mechanical strength of femurs from Gsn+/+ and Gsn−/− mice. (a) Graphic representation of the data generated by four-point bending test. The slope of the line relating bending and displacement is a reflection of stiffness or rigidity, and the area under the curve is the energy required to produce failure. (b) The ultimate moment-displacement curves for +/+ and −/− femurs. The normalized displacement at failure (ultimate) was greater in the Gsn−/− femurs (see Table ). (c) The energy required to produce failure was greater in the femurs from Gsn−/− mice (see Table ).
Mentions: The imbalance between bone resorption and formation and the increased mineralization reported here may have affected bone strength, and the ability of the skeleton to resist damage (fracture) may be altered. To test this possibility, we performed four-point bending tests of mouse bones to assess their mechanical strength, as described in Materials and Methods. As shown in Fig. 11 and Table , the Gsn−/− bones required greater energy and greater maximal displacement to produce femoral failure compared with the Gsn+/+ femurs. Changes in bone stiffness resulting from over mineralization and decreased remodeling seen in some osteopetroses were not observed in the bones from the Gsn−/− mice.

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