Biomedical Engineering Reference
In-Depth Information
receptors (Fgfr1-Fgfr4).
Fgfr1 is expressed in hypertrophic chondrocytes
and Fgfr1 signalling has stage-specific effects on osteoblast maturation: it
acts to stimulate differentiation in osteoprogenitor cells, whereas it functions
to arrest the maturation of differentiated osteoblasts.
64
FGFs 2, 9 and 18
probably bind Fgfr1 in osteoblasts. although FGFs 9 and 18 represent the
predominant signals during embryo development, FGF2 seems to be the
most relevant in postnatal stages. in differentiated osteoblast, FGF2 activates
runx2 via MapK pathway and plays an important role in the regulation of
mineralization and bone formation.
Fgf2r is expressed in reserve chondrocytes
and appears to be downregulated in proliferating chondrocytes. Fgf2r shows
tissue specific alternative splicing, resulting in epithelial variants (b forms) and
mesenchymal variants (c forms). Studies of the ligand binding demonstrate
that FGF7 and 10, activate Fgfr2b, whereas FGF2, 4, 6, 8 and 9 activate
Fgfr2c.
FGF18 acts as a physiological ligand for Fgfr3, which regulates cell
growth and differentiation of proliferating chondrocytes, while in differentiated
osteoblasts it regulates bone density and cortical thickness.
65
3.4.5 Ephrin signalling
Ephrins have a capacity for bidirectional signalling. thus, when a cell
expressing an ephrin receptor contacts a cell expressing an ephrin ligand,
signals are transduced into both the cells by forward and reverse signalling,
respectively. there are two classes of ephrins, the B class (B1 to B3) are
ligands for EphB1-6 tyrosine kinase receptors, whereas class a ephrins
(a1 to a5) are ligands for Gpi-anchored Epha receptors (a1 to a10). in
bone biology, ephrinB and its receptors control skeleton development.
66
a
bidirectional signalling is also implicated in the communication between
osteoblasts and osteoclasts: the ephrinB2 ligand in osteoclasts and EphB4
receptor in osteoblasts are responsible for a forward-reverse signalling which
regulates osteoblast-osteoclast cooperation. the reverse signalling from EphB4
in osteoblasts to ephrinB2 in osteoclast progenitors leads to the inhibition
of osteoclast differentiation, while the forward signalling through EphB4
induces osteogenic regulatory factors, such as dlx5, osx and runx2.
67
3.4.6 Mitogen-activated protein kinases (MAPK)
signalling pathway
MAPKs are important signal transducing serine/threonine-specific protein
kinases that are involved in many facets of cellular regulation. the MapK
pathway is activated by a variety of growth factors with a role in osteogenesis,
including FGF, pdGF, tGFb and iGFs. the extracellular stimuli lead to
activation of a signalling cascade composed of Map kinase, Map kinase
kinase (MKK or Map2K) and Map kinase kinase kinase (MKKK or Map3K).
