Begell House Inc.
Critical Reviews™ in Eukaryotic Gene Expression
CRE
1045-4403
12
3
2002
Approaches for Skeletal Gene Therapy
11
10.1615/CritRevEukaryotGeneExpr.v12.i3.10
Christopher
Niyibizi
Department of Orthopaedic Surgery, Ferguson Laboratories for Orthopaedic Research, Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
Corey J.
Wallach
Department of Orthopaedic Surgery, Ferguson Laboratories for Orthopaedic Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
Zhibao
Mi
Ferguson Laboratories for Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
Paul D.
Robbins
Ferguson Laboratories for Molecular Genetics and Biochemistry, Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
The role of gene therapy in the treatment of musculoskeletal disorders continues to be an active area of research. As the etiology of many musculoskeletal diseases becomes increasingly understood, advances in cellular and gene therapy may be applied to their potential treatment. This review focuses on current investigational strategies to treat osteogenesis imperfecta (OI). OI is a varied group of genetic disorders that result in the diminished integrity of connective tissues as a result of alterations in the genes that encode for either the proal or proa2 component of type I collagen. Because most forms of OI result from dominant negative mutations, isolated gene replacement therapy is not a logical treatment option. The combined use of genetic manipulation and cellular transplantation, however, may provide a means to overcome this obstacle. This article describes the recent laboratory and clinical advances in cell therapy, highlights potential techniques being investigated to suppress the expression of the mutant allele with antisense gene therapy, and attempts to deliver collagen genes to bone cells. The challenges that the investigators face in their quest for the skeletal gene therapy are also discussed.
Cellular Actions and Signaling by Endostatin
17
10.1615/CritRevEukaryotGeneExpr.v12.i3.20
Ramam
Ramchandran
1Divisions of Nephrology, Department of Medicine and Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
S. Ananth
Karumanchi
Divisions of Nephrology, Department of Medicine and Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
Jun-ichi
Hanai
Divisions of Nephrology, Department of Medicine and Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
Seth L.
Alper
Divisions of Nephrology, and Molecular Medicine, Department of Medicine and Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
Vikas P.
Sukhatme
Divisions of Nephrology, and Hematology-Oncology, Department of Medicine and Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
The malignant transformation of a normal cell into a cancer cell requires no vasculature. Growth of solid tumors, however, requires angiogenesis to provide oxygen and nutrients to support cell proliferation. The switch from an avascular to a vascular phenotype is typically associated with acceleration of tumor growth. Antiangiogenic therapy, starving a tumor of its blood supply, is an attractive addition to the anticancer armamentarium. Animal tests of antiangiogenic therapy have shown remarkable potential. Initial human trials have proven antiangiogenic therapy to be remarkably nontoxic. Numerous antiangiogenic agents have been isolated as proteolytic fragments of endogenous polypeptides of the extracellular matrix. Endostatin was the first such antiangiogenic protein described and its potent antitumor effects in mice have generated wide interest. This review summarizes recent advances in endostatin biology and highlights new results on the cellular and subcellular mechanisms of endostatin action.
The Role of the Androgen Receptor in Prostate Cancer
15
10.1615/CritRevEukaryotGeneExpr.v12.i3.30
Donald J.
Tindall
Departments of Urology and Biochemistry/Molecular Biology, Mayo Clinic, Rochester, MN 55905
Haojie
Huang
Departments of Urology and Biochemistry/Molecular Biology, Mayo Clinic, Rochester, MN 55905
Androgens are important not only for the development and function of the normal prostate gland, but also for the maintenance of prostate cancer (PCa) cells. The biological function of androgens is exerted by activation of the transcriptional activity of the androgen receptor (AR). The function of the AR in the prostate is largely dependent on AR protein levels and structural integrity of the protein and other transcription activation factors. Based upon the clinical findings that androgen ablation therapy-resistant PCa still expresses AR and the androgen-regulated gene, prostate-specific antigen, a concept is developing that the androgen receptor is critical for androgen-refractory prostate cancer cells. Indeed, because of the alterations detected in the AR gene, many noncognate activators, including estrogen, progesterone, peptide growth factors, and cytokines, are able to induce transactivation of the AR under androgen-depleted conditions. Also, transactivational activity of the AR is often modulated by crosstalk between the AR and other signaling pathways in cancerous prostatic cells. Dysregulation of AR function in prostate cancer results in an abnormal profile of AR-regulated genes, which include cell cycle regulators, transcription factors, and those proteins important for cell survival, lipogenesis, and secretion. Thus in this review we will evaluate the significance of the AR in the development and progression of prostate cancer.
Scaffolds for Tissue Engineering of Cartilage
28
10.1615/CritRevEukaryotGeneExpr.v12.i3.40
T. B. F.
Woodfield
IsoTis N.V., PO Box 98, 3720 MB Bilthoven, The Netherlands, and Institute for Biomedical Technology, University of Twente, PO Box 217, 7500 AE Enschede, The Netherlands
J. M.
Bezemer
IsoTis N.V., PO Box 98, 3720 MB Bilthoven, The Netherlands
J. S.
Pieper
IsoTis N.V., PO Box 98, 3720 MB Bilthoven, The Netherlands
C. A.
van Blitterswijk
IsoTis N.V., PO Box 98, 3720 MB Bilthoven, The Netherlands, and Institute for Biomedical Technology, University of Twente, PO Box 217, 7500 AE Enschede, The Netherlands
J.
Riesle
IsoTis N.V., PO Box 98, 3720 MB Bilthoven, The Netherlands
Articular cartilage lesions resulting from trauma or degenerative diseases are commonly encountered clinical problems. It is well-established that adult articular cartilage has limited regenerative capacity, and, although numerous treatment protocols are currently employed clinically, few approaches exist that are capable of consistently restoring long-term function to damaged articular cartilage. Tissue engineering strategies that focus on the use of three-dimensional scaffolds for repairing articular cartilage lesions offer many advantages over current treatment strategies. Appropriate design of biodegradable scaffold conduits (either preformed or injectable) allow for the delivery of reparative cells, bioactive factors, or gene factors to the defect site in an organized manner. This review seeks to highlight pertinent design considerations and limitations related to the development, material selection, and processing of scaffolds for articular cartilage tissue engineering, evidenced over the last decade. In particular, considerations for novel repair strategies that use scaffolds in combination with controlled release of bioactive factors or gene therapy are discussed, as are scaffold criteria related to mechanical stimulation of cell-seeded constructs. Furthermore, the subsequent impact of current and future aspects of these multidisciplinary scaffold-based approaches related to in vitro and in vivo cartilage tissue engineering are reported herein.