Bone Healing and Failure - Engineered Bone: Tissue Engineering Intelligence Unit - page 50

The FGFs have a mitogenic effect on fibroblasts, chondrocytes and osteoblasts and this is
thought to be their primary role. 42,43 FGF-1 appears to primarily affect chondrocytes as its
peak expression correlates with peak chondrogenesis. FGF-1 has been shown to increase callus
volume in a rat femur segmental defect model. 41 FGF-2 has greater mitogenic and angiogenic
potency than FGF-1. It is thought to have a role in chondrocyte maturation and endochondral
bone formation. It may also have a role in bone resorption. FGF-2 treatment has been shown
to increase callus size in canine and diabetic rat models. 44,45 Other studies have failed to show
an effect, however the timing of FGF treatment would appear to be critical. If FGFs are admin-
istered within the first 24 hours following fracture then an increase in callus size occurs. 44-46
When FGF-2 was applied to fresh rabbit fibular osteotomies it resulted in the stimulation of
callus formation, increased bone formation, and earlier restoration of mechanical strength at
the fracture site. 46
Insulin-Like Growth Factor
The IGF family consists of two polypeptides known as IGF-I and IGF-II both of which
have been shown to promote cellular proliferation and matrix synthesis by osteoblasts and
chrondroblasts. IGF-II is 50-100 times more abundant in human bone compared to IGF-I
however IGF-I is 4 to 7 times more potent and is more dependent on growth hormone. IGF-I
may participate in endochondral fracture repair. Studies suggest that it accelerates the repair of
intramembraneous bone defects. 47 IGF-II may also play a similar role in fracture healing, how-
ever, further studies are required to determine the exact role of these factors.
Platelet-Derived Growth Factor
PDGF is a dimeric molecule consisting of disulfide bonded A- and B- polypeptide chains.
It can exist either as a homodimeric (PDGF-AA or -BB) or a heterodimeric form (PDGF-AB).
The different PDGF isoforms exert their effect on target cells by binding with different speci-
ficity to two structurally related protein tyrosine kinase receptors denoted as the α and β recep-
tors. 48 PDGF is initially released by degranulating platelets in the fracture hematoma and may
be important in promoting chemotaxis. 49,50 Homodimeric PDGF-AA predominates in the
early phases and is expressed by macrophages in addition to that released by platelets. This is
also detectable in both early and mature chondrocytes. 7 PDGF-BB is the primary isotype seen
in osteoblasts. 7 PDGF has been shown to increase callus density and mechanical strength in a
rabbit tibial osteotomy model. 51 Histologically PDGF treated osteotomies revealed a more
advanced stage of osteogenic differentiation as compared to controls. PDGF may also have a
role in bone resorption. Zhang et al 52 have shown the PDGF promotes adult osteoclast bone
resorption directly through the PDGF- β receptor. A dose dependent relationship between vol-
ume of Howship's lacuna and quantity of resorption pits was established. PDGF influences
expression of IL-6, a key cytokine that induces osteoclast recruitment. This role is mediated
through the activation of transcription factors through interaction between PDGF and PDGF- β
receptor located on osteoblasts.
Transforming Growth Factor β Superfamily
The TGF- β superfamily is a large group of structurally related polypeptides that includes
multiple isoforms of TGF- β s, BMPs and GDFs. Several members of the subfamilies have been
shown to promote the differentiation of mesenchymal stem cells into the osteogenic and chon-
drogenic lineages. A number of BMPs have been shown to promote bone repair both in con-
trolled animal models of fracture healing, segmental defects and spinal fusion, and in clinical
trials. 53-76 The prerequisite for their successful action is the presence of responding cells. The
role of these factors in fracture healing is becoming increasingly understood. Bostrom et al 77
were one of the first investigators to describe the temporal expression of BMP-2 and -4 during
fracture healing.