Effect of interleukin-6 secreted by engineered human stromal cells on osteoclasts in human bone

Sandhu, Jagdeep Singh; Gorczynski, Reg; Waddell, Jennifer; Nguyen, Hai P.; Squires, J; Boynton, Erin; Hozumi, N

doi:10.1016/s8756-3282(98)00172-0

Cited by 15 publications

(14 citation statements)

References 29 publications

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“…2 Gene therapy also allows the targeted delivery of protein to specific cells, thus increasing the efficacy of the desired protein at the specific target site. 3 So far, the most efficient vectors for gene delivery are viruses. The osteoinductive activity induced by retroviral-mediated BMP2 or BMP7 gene therapy has been demonstrated both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy for new bone formation using adeno-associated viral bone morphogenetic protein-2 vectors

et al. 2003

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Previous reports have suggested that bone morphogenetic protein (BMP) gene therapy could be applied for in vivo bone regeneration. However, these studies were conducted either using immunodeficient animals because of immunogenicity of adenovirus vectors, or using ex vivo gene transfer technique, which is much more difficult to handle. Adenoassociated virus (AAV) is a replication-defective virus without any association with immunogenicity and human disease. This study was conducted to investigate whether orthotopic new bone formation could be induced by in vivo gene therapy using AAV-based BMP2 vectors. To test the feasibility of this approach, we constructed an AAV vector carrying human BMP2 gene. Mouse myoblast cells (C2C12) transduced with this vector could produce and secrete biologically active BMP2 protein and induce osteogenic activity, which was confirmed by ELISA and alkaline phosphatase activity assay. For in vivo study, AAV-BMP2 vectors were directly injected into the hindlimb muscle of immunocompetent SpragueDawley rats. Significant new bone under X-ray films could be detected as early as 3 weeks postinjection. The ossification tissue was further examined by histological and immunohistochemical analysis. This study is, to our knowledge, the first to establish the feasibility of AAV-based BMP2 gene therapy for endochondral ossification in immunocompetent animals.

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Section: Introductionmentioning

confidence: 99%

Gene therapy for new bone formation using adeno-associated viral bone morphogenetic protein-2 vectors

et al. 2003

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“…In addition, transgenic mice broadly expressing IL-6 with high circulating levels of IL-6 protein did not display increased osteoclast formation or bone resorption (25). Nonetheless, when human bone marrow cells engineered to express IL-6 were implanted into human bone in SCID mice, osteoclast surface was increased (44). When cells expressing IL-6 were injected intraperitoneally, circulating IL-6 levels were increased but osteoclast surface was not, suggesting that local expression of IL-6 in bone may be critical for influencing bone resorption (44).…”

Section: Discussionmentioning

confidence: 99%

IL-6 is not required for parathyroid hormone stimulation of RANKL expression, osteoclast formation, and bone loss in mice

O’Brien

Jilka

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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“…3) suggest that SP500263 will be a potent inhibitor of IL-6 gene expression in bone. IL-6 is a critical osteotropic factor involved in the differentiation and activation of osteoclasts leading to increased bone resorption and as such may be an integral factor in the pathogenesis of osteoporosis (Grey et al, 1999;Sandhu et al, 1999). Therefore, SP500263 represents a member of a novel series of SERMs that may have clinical use in treating and preventing postmenopausal osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

“…IL-6 is a cytokine produced by many cell types, including fibroblasts, endothelial cells, keratinocytes, monocytes, T cells, mast and tumor cell lines, and cells of neural origins (Van Snick, 1990;Kishimoto et al, 1995;Sehgal et al, 1995;Keller et al, 1996). IL-6 is believed to be involved in the pathogenesis of numerous diseases, including inflammatory conditions (rheumatoid arthritis, inflammatory bowel disease, encephalitis), cancer (leukemia, renal cell carcinoma, prostate cancer, multiple myeloma), and osteoporosis (Tsukamoto et al, 1992;Eustace et al, 1993;Weissglas et al, 1997;Alonzi et al, 1998;Hobisch et al, 1998;Chung et al, 1999;Grey et al, 1999;Nishimoto et al, 1999;Sandhu et al, 1999). On the other hand, mice with a genetic knockout of the IL-6 gene have no major health defects (Kopf et al, 1994;Poli, 1998).…”

Section: Sp500263 Does Not Activate Gene Expression Through An Erementioning

confidence: 99%

Differential Response of Estrogen Receptors α and β to SP500263, a Novel Potent Selective Estrogen Receptor Modulator

Brady¹,

Doubleday²,

Gayo‐Fung³

et al. 2002

Mol Pharmacol

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We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) ␣ and the more recently cloned ER-␤. Because of the high homology of amino acid residues in the ligand-binding domain of ER-␣ and ER-␤, we were not surprised to find that SP500263 binds to both ERs equally well. In contrast, SP500263 acts as a strong estrogen agonist in a strictly ER-␣-specific manner in U2OS osteosarcoma cell lines blocking the production of interleukin (IL) 6 and granulocyte macrophage colony-stimulating factor. SP500263 also blocked IL-6 production in primary bone cells. The mechanism of this inhibition is different from the classic estrogen stimulation involving an estrogen response element (ERE). SP500263 does not activate gene expression through an ERE.In contrast to the results observed in U2OS cells, SP500263 acts as a strong estrogen antagonist in an MCF-7 breast cancer proliferation assay. Therefore, SP500263 is a member of a series of next-generation SERMs with functional selectivity toward ER-␣ and a mixed agonist/antagonist profile in a bone cell assay versus a breast cancer assay. The panel of assays described herein allow for the development of receptor-specific ligands that may be further developed into novel pharmaceuticals with an improved profile for the treatments of osteoporosis and breast cancer.

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Effect of interleukin-6 secreted by engineered human stromal cells on osteoclasts in human bone

Cited by 15 publications

References 29 publications

Gene therapy for new bone formation using adeno-associated viral bone morphogenetic protein-2 vectors

Gene therapy for new bone formation using adeno-associated viral bone morphogenetic protein-2 vectors

IL-6 is not required for parathyroid hormone stimulation of RANKL expression, osteoclast formation, and bone loss in mice

Differential Response of Estrogen Receptors α and β to SP500263, a Novel Potent Selective Estrogen Receptor Modulator

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