Biomedical Engineering Reference
In-Depth Information
Figure 2.3.
Schematic summary of the stages of fracture repair and their associated molecular processes. The relative temporal
aspects of each of the stages of the fracture healing process are denoted by basic geometric shapes that also connote the relative
intensity of the molecular processes that define each of the stages. The relative levels of expression of various mRNAs that have
been examined in our laboratories are denoted by three line widths. The levels of expression are in percent over baseline for each
and are not comparable for the various mRNAs. Data for expression levels for the proinflammatory cytokines and the extracellullar
matrix (ECM) mRNAs are from Kon et al., 2001 [118]; data for TGF-
family members are from Cho et al., 2002 [38]; data for prote-
ases and angiogenic factors from are from Lehmann et al., 2002 [127]; and data for Cox2 are from Gerstenfeld et al., 2002 [70].
Data pertaining to Ihh and iNOs expression are unpublished. M-CSF, macrophage colony-stimulating factor; IL, interleukin; RANKL,
RANK ligand; OPG, osteoprotegrin; INF, interferon; TNF, tumor necrosis factor; VEG1, xxx; TGF, transforming growth factor; BMP,
bone morphogenetic protein; GDF, growth and differentiation factor; Ihh, Indian hedgehog; PTHrP, parathyroid hormone-related
peptide; MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor; Ang, angiopoietin. Reproduced with permission
from Gerstenfeld LC, Cullinane DM, Barnes GL, et al. Fracture healing as a post-natal developmental process: molecular, spatial,
and temporal aspects of its regulation. J Cell Biochem. 2003 Apr 1;88(5):873-84. Copyright © 2003 Wiley-Liss, Inc., A Wiley
Company.
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Table 2.1.
Comparison of strategies in the development of therapeutic agents to treat osteoporosis versus fracture and bone
repair
A. Stages of fracture repair and strategies to enhance fracture repair
Initial injury
Endochondral formation
Primary bone formation
Secondary bone formation
Inflammation
Periosteal response
Cartilage resorption
Coupled remodeling
Factors that promote
Increase ratio of bone/
Factors that change rates of
Factors that enhance coupled
stem-cell recruitment
cartilage differentiation
endochondral remodeling
bone formation (TNF family)
(PTH, BMPs) (FGFs, Wnts, PTH) (TNF family)
B. Stages of coupled remodeling and strategies to enhance bone mass
Activation
Diminish numbers of osteoclasts (TNF family)
Resorption
Diminish osteoclast activity/increase rate of osteoclast turnover (TNF family)
Formation
Increase osteoblast numbers/osteoblast activity (BMPs, PTH, Wnts)
2.5 Future Perspectives
on Therapeutic Uses of
Morphogenetic Factors
vidual factors has had mixed success in pro-
moting bone healing. Regaining biomechanical
competency more quickly is even more compli-
cated than promoting stem-cell differentiation.
Biomechanical competency involves many
factors, including the restoration of the mate-
rial properties of the tissue and of appropriate
skeletal-tissue geometry. At the same time, it
will be necessary to defi ne appropriate modali-
ties for using repair-promoting factors and to
identify when, where, and how long the factors
should be applied. Because many factors, once
they activate receptors, utilize overlapping
signal-transduction pathways to mediate intra-
cellular effects, signal pathways need to be
identifi ed in the hope of making optimal use of
the small-molecule pharmaceuticals that are
being developed.
Reduction of the morbidity associated with
some
% of fractures and improvement
of healing after osteotomies, arthrodeses,
spinal fusions, and other reconstructive ortho-
pedic procedures depend on better understand-
ing of the biology of fracture and bone healing
(
5
% to
10
). As discussed above, multiple morphoge-
netic factors regulate normal skeletal develop-
ment, but it is not clear how they function in
postnatal healing. Many factors act coopera-
tively or even antagonistically at different
stages of bone development. Single use of indi-
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