Download Osteogenesis Imperfecta

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. (2002).
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
FAUCI; BRANWALD; KASPER; HAUSER; LONGO; JAMESON; LOSCALZO. HARRISON’s, Principles of Internal
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
Byers PH. Osteogenesis imperfecta: perspectives and opportunities. Curr Opin Pediatr. 2000 Dec;12(6):603-9.
Review

Prockon DJ, Constantinou CD, Dombrowski KE, Hojima Y, Kadler KE, Kuivaniemi H, Tromp G, Vogel BE. “Type I
procollagen: the gene-protein system that harbors most of the mutations causing osteogenesis imperfecta and
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
http://www.fei.com/uploadedImages/Images/Image_Gallery/collagen_fibrils_from_knee_joint_capsule_157_lg
.jpg

http://upload.wikimedia.org/wikipedia/commons/thumb/d/d1/Collagentriplehelix.png/120pxCollagentriplehelix.png

Mitsuo Yamauchi and Marnisa Sricholpech (2012). “Lysine post-translational modifications of collagen”. Arch
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
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
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
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
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
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
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
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
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