Radioprotectant strategies: pediatric growth plate. Treatment of Fractures in Pathology Bone, Reconstructive Alternatives: Limb-Sparing Sarcoma Surgery, Genetics of Pagetoid Osteosarcoma
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Growth plate and bone radioprotection and radiorecovery
Our laboratory has been funded continuously by the NIH since 2000 for our work evaluating the mechanisms of damaging effects of irradiation on bone growth. Most recently, the focus has been on selective stimulation of radiorecovery pathways. This work involves in vitro and in vivo work with histomorphometric, immunohistochemical, and molecular evaluation at the RNA and protein level. This area of research is relevant to children being treated for bone and soft-tissue sarcomas.
Utilizing both in vitro and in vivo work including an orthotopic intraosseous osteosarcoma injection model, differential expression of genes and pathways related to metastatic potential are being evaluated.
Chemotherapy related osteoporosis
Our laboratory has established the high prevalence of premature low bone mineral density in young adults following chemotherapy for pediatric malignancies, including bone and soft-tissue sarcomas. However, the specific mechanisms of this adverse outcome have not been elucidated. Furthermore, the precise role of specific novel agents in the simultaneous treatment of osteosarcoma and low bone mineral density has yet to be explored, leaving room for exploration and development of new treatments.
Radiation associated fractures
Building upon our extensive experience exploring the damaging effects of irradiation treatments on growth plate function in pediatric patients with malignant bone and soft-tissue tumors, an in vivo nude mouse model has been established to evaluate the more common problem of fracture following bone irradiation. This problem spans numerous specialties, including gynecologic oncology, where pelvic irradiation frequently leads to pelvic stress fractures, as well as pediatric oncology, adult oncology, radiation oncology, and orthopedics.
Selected references (please refer to PubMed link for complete list)
Arrington S, Damron TA, Mann KA, Allen MJ. Concurrent administration of zoledronic zcid and irradiation leads to improved bone density, microarchitecture and biomechanical strength in a mouse model of tumor-induced osteolysis. Accepted for publication in J Surg Oncol, November 2007.
Arrington SA, Schoonmaker JE, Damron TA, Mann KA, Allen MJ. Temporal changes in bone mass and mechanical properties in a murine model of tumor osteolysis. Bone 2006 Mar;38(3):359-67. 2005 Nov 5
Damron TA, Horton J, Naqvi A, Loomis RM, Margulies BS, Strauss JA, CE Farnum, Spadaro JA. Combination radioprotectants maintain chondrocyte proliferation better than single agents by decreasing early parathyroid hormone related protein changes after growth plate irradiation. Radiation Research 2006 Mar;265(3):350-8.
Damron TA, Ward WG, Stewart A. Osteosarcoma, chondrosarcoma, and Ewings sarcoma: National Cancer Database Report. Clin Orthop Relat Res [Epub ahead of print 2007 Mar 22] 459:40-47, 2007.
Horton JA, Bariteau JT, Loomis RM, Strauss JA, Damron TA. Ontogeny of skeletal maturation in the juvenile rat. Anat Rec.2008 Mar;291(3):283-92.
Horton JA, Margulies BS, Strauss JA, Bariteau JT, Damron TA, Spadaro JA, Farnum CE. Restoration of growth plate function following radiotherapy is driven by increased proliferative and synthetic activity of expansions of chondrocytic clones. J Orthop Res [Epub ahead of print 2006 Aug 17] 2006 Oct;24(10):1945-56.
Margulies BS, Horton JA, Wang Y, Damron TA, Allen MJ. Effects of radiation therapy on chondrocytes in vitro. Calcif Tissue Int. 2006 May;78(5):302-13. Epub 2006 May 9.
Spadaro JA, Damron TA, Horton JA, Margulies BS, Murray GM, Clemente DA, Strauss JA. Density and structural changes in the bone of growing rats after weekly alendronate administration with and without a methotrexate challenge. J Orthop Res. 2006 May;24(5):936-44.
Spadaro JA, Horton JA, Margulies BS, Strauss JA, Farnum CE, Damron TA. Radioprotectant combinations spare radiation-induced damage to the physis more than fractionation alone. International Journal of Radiation Biology, 2005 Oct;81(10):759-65.
Wang Y, Zhang M, Middleton FA, Horton JA, Pritchard M, Spadaro JA, Farnum CE, Damron TA. Connective tissue growth factor and insulin-like growth factor 2 show upregulation in early growth plate radiorecovery response following irradiation. Cells Tissues Organs. 2007;186(3):192-203. Epub 2007 Jul 12.
Zhang M, Wang Y, Middleton FA, Horton JA, Farnum CE, Damron TA. Growth plate zonal microarray analysis shows upregulation of extracellular matrix genes and down-regulation of metalloproteinsaes and cathepsins following irradiation. Connective Tissue International [Epub ahead of print 5 Jun 2007].