Biomedical Engineering Reference
In-Depth Information
Fig. 11.4
Schematic
of chondrocyte maturation
at the growth plate (
blue
)
showing the Ihh/PTHrP
negative feedback loop and
selected biomarkers.
Arrows
indicate positive regulation
and bars indicate negative
regulation
Endochondral bone formation is regulated by the autocrine/paracrine signaling
of Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP)
(Fig.
11.4
)[
81
-
83
]. Ihh is expressed by pre-hypertrophic and early hypertrophic
chondrocytes entering the early stages of terminal differentiation. This molecule
stimulates the proliferating chondrocytes by binding the membrane receptor
Patched (Ptch), which activates the membrane receptor Smoothened (Smo) and
stimulates synthesis of PTHrP. PTHrP expression then blocks further expression of
Ihh, establishing a negative feedback loop to provide fine control over the rate of
chondrocyte proliferation and maturation. The transcription factor Sox9 is a target
of PTHrP in the growth plate that likely influences maintenance of a stable
proliferating chondrocyte phenotype [
84
]. Sox9 has also been implicated in later
stages of chondrocyte hypertrophy [
85
]. Precise spatial and temporal control over
these and other extracellular signaling molecules and transcription factors is critical
to endochondral bone development.
Ihh expression in chondrocyte cultures is upregulated in response to tensile
stretching and is required for increased proliferation [
86
]. This mechanoresponse
gene is mediated downstream by BMP 2 and 4 and does not involve PTHrP. PTHrP
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