Bone Healing and Failure - Engineered Bone: Tissue Engineering Intelligence Unit - page 52

The specific roles of each of the other members of the TGF- β superfamily are becoming
clearer. It has been shown that BMP-3 can induce ectopic endochondral ossification in rats. 79
It may also have a role in chondrogenesis gives its ability to induce chondrogenic phenotypic
expression in various cells. 80-82 Recent data suggests that BMP-3 may be an antagonistic regu-
lator of osteogenic BMPs. 83,84 Cho et al 10 found BMP-3 to be maximally expressed during the
period of peak osteogenesis and suggested that it may have a regulatory function here.
GDF10 (BMP-3b) is closely related to BMP-3 and is up-regulated on day 7 and 21 follow-
ing fracture, it may have a role in both intramembraneous ossification and chondrogenesis. 10
BMP-5 and -6 show a strong and persistent expression during the first 3 weeks of fracture
healing. 10 Developmental studies have shown roles for these factors in the regulation of mesen-
chymal condensation and endochondral progression and in the stimulation of chondrocyte
maturation. 85-90 BMP-6 appears to be an autocrine factor initiating chondrocyte maturation, a
role it may share with BMP-2. 91 BMP-7 and -8 (OP-I and OP-2) are similar in structure. Both
of these factors show a high restricted expression pattern during fracture healing that parallels
the osteogenic phase of fracture healing at the time when bone formation is maximal and
resorption of calcified cartilage is taking place. 10
GDF expression during fracture healing has been outlined above. It would appear that
GDF-5 is important in chrondrogenesis during fracture repair as its expression is restricted to
this phase. 10 This correlates with developmental studies, 91 and studies that have shown potent
chondrogenesis with ectopic implantation of GDF-5. 92 Restricted GDF-8 expression during
day 1 of fracture healing implies its presence in primitive mesenchymal stem cells and its po-
tential role as an autocrine inhibitor of myogenic lineage differentiation. 10
The expression of TGF- β in fracture healing is well documented. 10,38,94-96 These factors are
produced by a variety of cells including osteocytes, osteoblasts and chondrocytes. Cho et al 10
using multiprobe ribonuclease protection assay (RPA) were able to compare the relative expres-
sions of several of the TGF- β isoforms. It would appear the TGF- β 2 and - β 3 function during
chondrogenesis and play more important roles than TGF- β 1.
The actions of the BMPs are mediated through a heteromeric receptor complex of type I
(BMPR-IA, or -IB or ALK-2/ActR-I), and type II (BMPR-II, ActR-II or ActR-IIB) recep-
tors. 97,98 Once activated, the receptor complex transduces signals intracellularly through acti-
vation of specific Smad proteins 97-99 which form heteromeric complexes that accumulate in
the nucleus where they participate in regulation of gene expression. 97 The Smad proteins can
be subdivided in three groups: the signal transducing receptor regulated Smads (R-Smads, e.g.,
Smad1, Smad2, Smad3, Smad5 and Smad8), the common mediator Smads (coSmads such as
Smad4) and the inhibitory Smads (I-Smads, e.g., Smad6 and Smad7). Whereas Smad2 and
Smad3 function in the signaling by TGF- β and activin, Smad1, Smad5 and Smad8 are in-
volved in BMP-signaling. 97-99
The temporal and spatial activation of specific Smad proteins during fracture healing re-
quires further investigation. This may give an even more accurate picture of the sequential
importance of the various growth factors as detection of activated Smad indicates a definite
effect of a growth factor in terms of altering gene expression.
The role of growth factor inhibitors in fracture repair remains unclear. However, inhibitors
such as noggin appear to have a role in the regulation of callus formation. 40 The importance of
growth factor inhibitors in the pathogenesis of fracture nonunion is unknown at present.
Failure of the Bone Repair Process
Despite considerable advances in our knowledge of the biological mechanisms of fracture
healing, delayed union and nonunion remain a significant clinical problem in certain patient
groups. While the precise mechanisms of bone repair failure at a cellular level remain largely
undetermined many of the factors that contribute to this failure are well recognized and under-
stood. These can be broadly categorized into general systemic factors and local factors pertain-
ing to the fracture site itself.