Skeletal response to lentiviral mediated gene therapy in a mouse model of MPS VII.

Mucopolysaccharidosis VII (MPS VII) is an autosomal recessive, lysosomal storage disorder caused by β-glucuronidase (GUSB) deficiency, resulting in the accumulation of glycosaminoglycans (GAGs), in a variety of cell types. Severe, progressive skeletal pathology, termed dysostosis multiplex, is a prominent clinical feature of MPS VII. We have evaluated a gene therapy protocol for its efficacy in preventing the development and progression of bone pathology in MPS VII mice treated with a lentiviral vector at birth or at 7 weeks.

Microarray expression analysis of genes and pathways involved in growth plate cartilage injury responses and bony repair.

The injured growth plate cartilage is often repaired by a bone bridge which causes bone growth deformities. Whilst previous studies have identified sequential inflammatory, fibrogenic, osteogenic and bone remodelling responses involved in the repair process, the molecular pathways which regulated these cellular events remain unknown. In a rat growth plate injury model, tissue from the injury site was collected across the time-course of bone bridge formation using laser capture microdissection and was subjected to Affymetrix microarray gene expression analysis.

Roles of Wnt signalling in bone growth, remodelling, skeletal disorders and fracture repair.

Wnt signalling has an essential role in regulating bone formation and remodelling during embryonic development and throughout postnatal and adult life. Specifically, Wnt signalling regulates bone formation by controlling embryonic cartilage development and postnatal chondrogenesis, osteoblastogenesis, osteoclastogenesis, endochondral bone formation, and bone remodelling. Abnormalities in the function of Wnt genes give rise to or contribute to the development of several pathological bone conditions, including abnormal bone mass, osteosarcomas and bone loss in multiple myeloma.

Cellular mechanisms for methotrexate chemotherapy-induced bone growth defects.

Methotrexate (MTX) is a commonly used anti-metabolite in childhood oncology and is known to cause bone growth arrest and osteoporosis; yet the underlying mechanisms for MTX-induced bone growth defects remain largely unclear. This study characterized damaging effects in young rats of acute chemotherapy with 5 once-daily doses of MTX (0.75 mg/kg) on the cellular activities in the growth plate in producing calcified cartilage and trabecular bone and on activities of osteoblastic cells in the metaphysis.