Biomedical Engineering Reference
In-Depth Information
can be quite complicated. TGF-
β
1 has been shown to promote collagen formation and increase
construct wet weight after four weeks
in vitro
[
394
,
399
]. However, the effectiveness of the growth
factor could be dependent on the differentiation state of the cells. For example, TGF-
β
1 stimulated
proliferation and proteoglycan synthesis in chondrocytes that have been cultured for a week
in vitro
,
but these effects were not apparent for freshly isolated chondrocytes [
401
]. Additionally, arthritic
chondrocytes experienced a decrease in proteoglycan synthesis when treated with TGF-
β
1[
402
].
In vitro
culture and disease have both been shown to affect the normal phenotypic expressions of
chondrocytes, so their response to biochemical stimuli is not surprisingly altered in comparison to
healthy cells
in vivo
.
BMPs play a major role in endochondral bone formation and show general effects on cellular
proliferation and matrix synthesis. As explained above, they are particularly attractive for cartilage
engineering studies because they affect both chondrogenesis and osteogenesis. Osteochondral inte-
gration is a critical factor in whether implants succeed or fail
in vivo
, so molecules that can stimulate
this response are desirable [
403
]. As with TGF-
β
, BMPs can act synergistically with mechanical
stimuli to accelerate regeneration of joint tissues. Currently, 20 types of BMPs have been identified,
but only a subset has been examined for cartilage regeneration. BMPs generally have the ability
to guide stem cells and immature bone and cartilage cells along the osteochondral pathway [
404
].
In experimental studies, BMP-1 showed greater stimulation of proteoglycan and collagen synthe-
sis than TGF-
β
1[
404
]. BMP-2 upregulated proteoglycan and collagen expression in chondro-
cytes [
403
,
405
,
406
] while also inducing better healing of defects
in vivo
[
398
,
403
]. BMP-4 showed
an ability to stimulate proteoglycan synthesis, bone formation, and cellular proliferation [
403
,
407
].
BMP-7 also showed positive effects on matrix synthesis [
403
] and proliferation [
408
] while also
decreasing collagen type I expression and suppressing infiltration of fibroblasts
in vivo
[
409
]. Artic-
ular chondrocytes treated with either BMP-12 or -13 synthesized elevated levels of GAG although
these increases were less than that observed for cells treated with BMP-2 [
405
]. Overall, experimen-
tal results have shown that BMPs have a generally positive effect on cartilage differentiation and
morphogenesis whether alone or in combination with other growth factors. For example, BMP-2
application with IGF-I resulted in over a 1-fold increase in aggregate modulus, accompanied by
increases in GAG production, as compared to controls [
387
].
The TGF-
β
superfamily also includes several other groups of growth factors known to af-
fect cartilage growth and differentiation. Cartilage derived morphogenetic proteins (CDMPs), os-
teogenic proteins (OPs), and growth differentiation factors (GDFs) have all been investigated as
possible means to accelerate regeneration of joint tissues
in vitro
and
in vivo
. Some of the growth fac-
tors included in these groups are actually the same molecule. For example, the pairs OP-1/BMP-7,
CDMP-1/GDF-5, and CDMP-2/GDF-6 are the same growth factors with alternate designations.
All of these molecules can affect chondrocytes in a manner similar to other TGF-
β
superfamily
members. OP-1, CDMP-1, and CDMP-2 all increase proteoglycan synthesis and cellular prolif-
eration [
410
] although OP-1 was found to be the more effective stimulus [
411
]. GDF-5, which is
naturally present in articular cartilage, also increases proteoglycan synthesis [
412
].
