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The effect of BMP-2 and its inhibitors on fracture repair
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Ng Kee Kwong, Fook Francois (2008) The effect of BMP-2 and its inhibitors on fracture repair. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2339768~S15
Abstract
The aims of this thesis were to investigate certain aspects of the regulation of
osteogenesis by BMPs and their physiological inhibitors; to determine whether the
balance between the two could have an effect on fracture repair; and to suggest
strategies for using this information to provide orthopaedic surgeons with better ways to
treat recalcitrant fractures .
BMP-2 and its inhibitor chordin were produced endogenously during the in vitro
osteogenic differentiation of human mesenchymal stem cells (MSCs) in response to
dexamethasone. The addition of exogenous BMP-2 increased the rate of osteogenic
differentiation of the MSCs. Knockdown of the BMP inhibitor chordin led to an
increase in the rate of osteogenic differentiation of human MSCs, secondary to an
increase in the bioavailability of BMP-2. These results raise the possibility that the
impaired healing of delayed- and non-unions reflects alterations in the ratios of BMPs to
their inhibitors. They further suggest that it may be possible to increase the rate of
osteogenesis, and thus improve fracture repair in vivo, by down-regulating the
endogenous production of BMP inhibitors.
To evaluate these possibilities further, the presence of BMP-2 and -14, as well as
their inhibitors chordin and noggin, were investigated by semi-quantitative
immunohistochemistry in human fracture biopsies. The expression of BMP-2, BMP-14,
chordin and noggin during fracture repair was demonstrated in areas of cartilage and
bone formation. Levels of expression of these proteins were compared between healing
and non-healing human fractures. There was a decreased relative expression of BMP-2
and BMP-14, compared to the BMP inhibitors, in the non-healing fractures v/s the
healing fractures. This suggests an imbalance between BMPs and their inhibitors in
fractures that do not heal. These data indicate novel ways to reduce rates of non-union
by the local application of BMP-2 or BMP-14, or the blocking of BMP antagonists.
Fracture healing may also be impaired by drugs used clinically. The antibiotic
tobramycin, commonly used to treat or prevent infections of bone, was shown to reduce
the osteogenic potential of human MSCs in vitro. An in vivo study was carried out to
determine whether a clinically relevant dose of tobramycin would impair fracture repair
induced by BMP-2. The biomechanical and radiological properties of the repair tissue,
induced by BMP-2 in a rat femoral defect model, were not affected by the presence of
tobramycin.
Overall, this thesis demonstrates that the balance between BMPs and their
inhibitors has a major influence on the rate of fracture repair and that this balance is
altered in non-healing fractures. The data suggest novel, clinically relevant, biological
strategies for enhancing bone healing.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology | ||||
Library of Congress Subject Headings (LCSH): | Bones -- Growth, Bone morphogenetic proteins, Fractures -- Treatment | ||||
Official Date: | November 2008 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Extent: | xix, 257 leaves : ill., charts | ||||
Language: | eng |
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