bone mineralization model
TRANSCRIPT
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Modeling Bone Mineralization in Osteogenesis Imperfecta Type VI
Jay Gopalakrishnan, Miao-jung Yvonne Ou, Lee Safranek, Erika Zuhr
Sean Bohun, Michael Lindstorm, Iain Moyles Svetlana Komarova, Marc McKee, Monzur
Murshed, Frank Rauch
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Osteogenesis Imperfecta Type VI
9 months 8 years 21 years
Homan et al, J Bone Miner Res 2011;26:2798
Hereditary disorder characterized by brittle bones
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Homan et al, J Bone Miner Res 2011;26:2798
OI Type VI – Mineralization delay
Size bars: 100μm
Normal histology No red
Patient histology Lots of red
Green – mineralized bone Red – unmineralized bone (osteoid)
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FREQ
UEN
CY
[% B
ON
E AR
EA]
0
1
2
3
4
5
6
10 15 20 25 30 CALCIUM CONCENTRATION [WEIGHT %]
Patient
Bone Mineral Density Distribution
Reference Curve (C.I. 95%)
Roschger et al, unpublished
OI Type VI – Increase in Material Bone Density
Patient Sex CaPeak z-score Patients from Glorieux et al, 2002
1 M +8.7
2 M +5.7
3 F +2.7
4 M +10.0
5 M +5.0
6 F +9.0
7 M +6.7
8 M +9.3
New Patients
9 M +8.7
Mean: +7.3
More low mineralized bone
More high mineralized
bone
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Mineralization schematics
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Normal OI type 6
Osteoblasts
Osteoid
Mineralized bone
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Normal OI type 6
Selected a uniformed region of collagen matrix Modeled changes in time within this small region
Approach 1
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Model schematics
Collagen (x1)
Mineral (y)
Assembled collagen matrix (x2)
Inhibitors (I)
Nucleators (N)
v1
k1
k2
k3
r1
r2
process
regulation
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Model assumptions • Collagen matrix is produced by osteoblasts in a naïve form
that requires further maturation into a fully assembled mature collagen matrix.
• Inhibitors of the mineralization are produced in the space near the cells and their availability is proportional to the amount of naïve collagen.
• Inhibitors are degraded, their degradation is stimulated by the presence of fully assembled collagen matrix.
• Nulceators arise in the assembled collagen, each collagen molecule gives rise to one nucleator. Nucleators are removed from the system when mineralization occurs.
• The rate of mineralization is directly proportional to the number of nucleators and is inversely related to the amount of inhibitors.
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Summary and Conclusions • We identified a number of parameters that can affect
either mineralization delay or degree of mineralization. • A single parameter (k1) describing the rate of matrix
maturation emerged as capable of both, increasing the mineralization delay and degree of mineralization.
• This is consistent with the experimental observations of similar histological phenotypes in two different conditions associated with delayed collagen assembly: 1) mutations within the C-propeptide cleavage site on collagen type I; 2) mutations in BMP-1, that cleaves C-propetide from collagen type I.
PEDF likely regulates the C-propeptide cleavage of collagen type I
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Future work
1. To define and track physical space occupied by collagen, non-collagenous proteins, water, and mineral.
2. To introduce additional source of nucleators to describe inter-fibrillar mineralization.
3. To better define parameters and validated assumptions using available or new experimental data.
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Normal OI type 6
Selected a larger region (~30 µm) of collagen matrix, linked to the cells on top
Modeled progression of the mineralization front
Approach 2