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476 results on '"Hankenson, Kurt D."'

111. Mutation in Osteoactivin Promotes Receptor Activator of NFκB Ligand (RANKL)-mediated Osteoclast Differentiation and Survival but Inhibits Osteoclast Function

Author

Abdelmagid, Samir M., primary, Sondag, Gregory R., additional, Moussa, Fouad M., additional, Belcher, Joyce Y., additional, Yu, Bing, additional, Stinnett, Hilary, additional, Novak, Kimberly, additional, Mbimba, Thomas, additional, Khol, Matthew, additional, Hankenson, Kurt D., additional, Malcuit, Christopher, additional, and Safadi, Fayez F., additional

Published
2015
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120. Leptin Functions Peripherally to Regulate Differentiation of Mesenchymal Progenitor Cells

Author

Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA ; 311 Hill Pavilion, 380 S. University Ave, University of Pennsylvania, Philadelphia, Pennsylvania 19103, USA, Scheller, Erica L., Song, Junhui, Dishowitz, Michael I., Soki, Fabiana Naomi, Hankenson, Kurt D., Krebsbach, Paul H., Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA, Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA ; 311 Hill Pavilion, 380 S. University Ave, University of Pennsylvania, Philadelphia, Pennsylvania 19103, USA, Scheller, Erica L., Song, Junhui, Dishowitz, Michael I., Soki, Fabiana Naomi, Hankenson, Kurt D., and Krebsbach, Paul H.

Abstract

Leptin functions through a well-documented central neuroendocrine pathway to regulate bone mass. However, the ability of leptin to modulate bone mass through a peripheral mechanism has been debated due to conflicting in vitro results and lack of sufficient in vivo models. We utilized mice with LoxP sites introduced into the long-form leptin receptor (ObRb) gene to determine how leptin regulates mesenchymal progenitor cell (MPC) differentiation and osteoblast function in vitro and in vivo . Rapid phosphorylation of Stat3 after leptin treatment of bone marrow stromal cells (BMSCs) from mice with conditional deletion of ObRb in macrophages (LysM Cre+F/F ) confirmed expression of functional leptin receptors by BMSCs. Adenovirus-Cre mediated disruption of ObRb in primary stromal cells decreased mineralization and increased adipogenesis. In contrast, BMSCs harvested from leptin-signaling deficient Ob/Ob or Db/Db mice showed increased mineralization. To determine the physiologic relevance of these differences, mice with cell-specific deletion of ObRb in mesenchymal precursors (3.6 Cre+F/F ) or osteoblasts (2.3 Cre+F/F ) were generated. Although the 2.3 Cre+F/F mice were grossly normal, the 3.6 Cre+F/F mice displayed mild obesity that was not attributed to food intake. Femurs of 3.6 Cre+F/F animals showed a 58%???61.9% increase in trabecular bone volume and a 65.5%???74% increase in bone mineral density. Cortical volume and mineral content were also increased 18%???22%. Primary 3.6 Cre+F/F BMSCs recapitulated the high mineralization phenotype of Ob/Ob and Db/Db BMSCs. We conclude that leptin may have multiple peripheral roles depending on the differentiation state of MPC. Leptin (a) helps maintain MPCs in an undifferentiated state and (b) promotes mineralization of more differentiated osteoblasts. S TEM C ells 2010;28:1071???1080

Published
2010

146. Thrombospondin 2 Inhibits Microvascular Endothelial Cell Proliferation by a Caspase-independent Mechanism

Author

Armstrong, Lucas C., Björkblom, Benny, Hankenson, Kurt D., Siadak, Anthony W., Stiles, Charlotte E., Bornstein, Paul, Armstrong, Lucas C., Björkblom, Benny, Hankenson, Kurt D., Siadak, Anthony W., Stiles, Charlotte E., and Bornstein, Paul

Abstract

The matricellular protein thrombospondin 2 (TSP2) regulates a variety of cell–matrix interactions. A prominent feature of TSP2-null mice is increased microvascular density, particularly in connective tissues synthesized after injury. We investigated the cellular basis for the regulation of angiogenesis by TSP2 in cultures of murine and human fibroblasts and endothelial cells. Fibroblasts isolated from murine and human dermis synthesize TSP2 mRNA and secrete significant amounts of immunoreactive TSP2, whereas endothelial cells from mouse lung and human dermis did not synthesize TSP2 mRNA or protein. Recombinant mouse TSP2 inhibited growth of human microvascular endothelial cells (HMVECs) mediated by basic fibroblast growth factor, insulin-like growth factor-1, epidermal growth factor, and vascular endothelial growth factor (VEGF). HMVECs exposed to TSP2 in the presence of these growth factors had a decreased proportion of cells in S and G2/M phases. HMVECs cultured with a combination of basic fibroblast growth factor, insulin-like growth factor-1, and epidermal growth factor displayed an increased proportion of nonviable cells in the presence of TSP2, but the addition of VEGF blocked this TSP2-mediated impairment of cell viability. TSP2-mediated inhibition of DNA synthesis by HMVECs in the presence of VEGF was not affected by the broad-spectrum caspase inhibitor zVAD-fmk. Similar findings were obtained with TSP1. Taken together, these observations indicate that either TSP2 or TSP1 can inhibit HMVEC proliferation by inhibition of cell cycle progression and induction of cell death, but the mechanisms responsible for TSP2-mediated inhibition of cell cycle progression are independent from those leading to cell death.

Published
2002
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