Biomedical Engineering Reference
In-Depth Information
the BMp/tGFb superfamily signalling is transduced through two types
of serine/threonine kinase receptors. three type i receptors have been shown,
namely type ia and iB BMp receptors (BMpr-ia or alK-3, and BMpr-iB
or alK-6) and type ia activin receptor (actr-ia or alK-2). three type ii
receptors for BMP have also been identified, including type II BMP receptor
(BMpr-ii) and type ii and iiB activin receptors (actr-ii and actr-iiB).
Whereas BMPR-IA, IB and II are specific to BMPs, ActR-IA, II and IIB are
also signalling receptors for activins.
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the BMpr-iB activity is necessary for
the initial steps of chondrogenesis, while BMpr-ia regulates the induction
of chondrocyte hypertrophy.
BMps transmit signals through Smad-dependent and Smad-independent
pathways, including ErK, JNK and p38/MapK pathways. there are three
classes of Smads: (1) receptor-regulated Smads (r-Smads) which can be
activated by BMp (BMpr-Smad), such as Smad 1, 5 and 8, or tGFß (tGFr-
Smad), such as Smad 2 and 3; (2) common partner BMp and tGFß mediator
Smads (Co-Smads), such as Smad 4; (3) inhibitory Smads, such as Smad 6
and 7.
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phosphorylated r-Smads bind to the common partner Smad-4. these
complexes translocate into the nucleus and regulate transcription of target
genes by interacting with various transcription factors and transcriptional
co-activators or co-repressors. BMpr-Smads facilitate expression of distal-
less homeobox 5 (dlx5) in osteoblasts, which induces expression of runx2
and osterix (osx) in osteoprogenitor cells. the inhibitory Smads negatively
regulate signalling by the r-Smads and Co-Smads.
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although the Smads
are critical mediators in the tGFß signalling pathway, BMp2 can activate
Smad-independent pathways, including Map kinases (ErK, JNK and p38)
which have distinct roles in regulating alkaline phosphatase and osteocalcin
expression in osteoblastic cells.
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3.4.3 Hedgehog signalling
indian hedgehog (ihh) is produced by pre-hypertrophic chondrocytes and
its signalling appears to act directly on osteoblast progenitors located in
the perichondrium.
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ihh signalling plays a crucial role in regulating the
temporal and spatial programme of early osteoblast commitment, but its role is
limited to this stage. in fact, when Smo (smoothened homolog) activity, which
encodes an obligatory component of the hh signaling pathway, is removed
in osx+ osteoblast precursors, normal bone osteoblasts are generated and the
endochondral skeleton at birth is indistinguishable from the wild type.
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3.4.4 Fibroblast growth factor (FGF) signalling
the FGF-family polypeptides play a critical role in regulating endochondral
and intramembranous ossification through four related tyrosine kinase
