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Ano letivo 2012-2013 Biologia celular e molecular II Cellular and molecular mechanisms in Osteogenesis imperfecta Luís Baptista, turma 2 Tânia Alves, turma 1 Tiago Barbosa, turma 2 Tiago Capela, turma 2 Osteogenesis Imperfecta • Osteogenesis imperfecta (OI) is a congenital bone disorder. • Caused by mutations affecting type I collagen. The molecule Collagen Fibrous proteins found in all multicellular animals Triple-stranded helical structure Repeating sequence of three amino acids glycine-X-Y (X and Y are often proline and hydroxyproline) 28 types of collagen identified and described 90% of the collagen in the body is of type I Main types found in connective tissue: types I, II, III, V and VI Collagen fibrils. These collagen fibrils are present in the joint capsule tissue that surrounds the knee. Collagen formation What genes are related to osteogenesis imperfecta? Mutations in the COL1A1, COL1A2, CRTAP, and LEPRE1 genes, as well as others. COL1A1 and COL1A2 genes The COL1A1 gene is located on the long (q) arm of chromosome 17 at position 21.33. The COL1A2 gene is located on the long (q) arm of chromosome 7 at position 22.1. CRTAP and LEPRE1 genes The CRTAP gene is located on the short (p) arm of chromosome 3 at position 22.3. The LEPRE1 gene is located on the short (p) arm of chromosome 1 at position 34.1. How do people inherit Osteogenesis imperfecta? • Most cases of cases have an autosomal dominant pattern of inheritance; • Sporadic mutations; • Less commonly, osteogenesis imperfecta has an autosomal recessive pattern of inheritance. Molecular defects OI type I • Over 90% of patients have mutations that reduce the synthesis of pro-α1 chains to about one half; • Mutations that reduce the synthesis of pro-α2 chains produce slightly more severe phenotypes; OI types II, III and IV • Mutations that produce structurally abnormal proα chains that have compromised assembly or abnormal folding of the triple helix; • “Procollagen suicide” One abnormal chain interacts with two normal chains Folding is prevented Accumulation of unfolded chains in the ER Enzimatic degradation Unfolded protein response (UPR) is estimulated Intracellular efects • Intracellular efects • Glycine’s replacement Replacement of glycine by a bulkier amino acid Production of poorly formed and unstable triple helices Disruption to helix folding Increasing of posttranslational hydroxylation and glycosylation of lysines Intracellular efects • Intracellular efects • Extracellular efects N-propeptide’s persistence Abnormal pro-α chains prevent normal processing of the N-propeptides N-propeptides persist Incorrect fibril assembly • Extracellular efects Collagen containing helix mutation can form insoluble aggregates in the ER that are degraded by the autophagosomeendosome system; Glycine substitutions in the N-terminal region tend to produce milder phenotypes; • Rare substitutions of charged amino acids or a branched amino acid in X- or Ypositions are lethal; What determines the patients’ phenotype? Hypothesis: gradient of phenotypic severity Symptoms Type I (Mild) Type II (Perinatal Lethal) Type III (Progressive Deforming) Type IV Diagnosis • Diagnosis is primarily based on clinical evidence; • The most frequent exams used to identifying the disease are: • X rays • Laboratory testing • Dual Energy X-ray Absorptiometry (DXA) • Bone Biopsy Treatments Currently prescribed • orthopaedic surgery ; • scoliosis management ; • rehabilitation, including water therapy and physical activity ; • Develop healthy lifestyle diet and exercise habits ; Treatments Currently being investigated: Treatments that are ineffective and are no longer prescribed: Pharmacologic Therapy Bisphosphonates Teriparatide Growth Hormone Inhibition of receptor activator of nuclear factor-kappaB ligand (RANKL) Cellular and Genetic Therapy Bone marrow transplantation Gene therapy • vitamin C • sodium fluoride • magnesium • anabolic steroids • calcitonin Bone formation and bone resorption Pharmacologic therapy Biphosphonates Synthetic analogues of pyrophosphate, like Pamidronate, Risedronate, Alendronate and zoledronic acid ; Inhibit osteoclast-mediated bone resorption on the endosteal surface of bone by: Teriparatide (Forteo) A synthetic form of the natural human Parathyroid Hormone (PTH) ; Intermittent administration of these drug would: • Increase bone mineral density and bone strength • Reduce the chance of getting a fracture In same cases, mainly in chilhood, there is an increase in the incidence of osteosarcoma, a malignant bone tumor Growth Hormone(GH) The effects of GH on bone cells are mediated through the functional GH receptors (GHRs) on osteoblast cells ; But, it also stimulates the insulin-like growth factor type 1 (IGF-1) production in liver and bone Osteoblast formation is increased and osteoblast apoptosis is inhibited Increase in bone turnover and formation Inhibition of receptor activator of nuclear factor-kappaB ligand (RANKL) It’s a member of the tumor necrosis factor (TNF) cytokine family ; It’s a ligand for osteoprotegerin(OPG) ; Key factor for osteoclast differentiation and activation ; The first FDA-approved RANKL inhibitor was Denosumab Cellular and Genetic Therapy Bone marrow transplantation contains both hematopoietic stem cells and mesenchymal stem cells (MSCs) latter precursors of osteoblasts Cellular and Genetic Therapy Gene Therapy Bibliography ALBERTS, Bruce; JOHNSON, Alexander; LEWIS, Julian; RAFF, Martin; ROBERTS, Keith; WALTER, Peter. 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