Identification of important interactions between subchondral bone ...
Identification of important interactions between subchondral bone ...
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still some controversy regarding the mechanism <strong>of</strong> action. Some<br />
data indicate a role for osteoclasts and others data indicate direct<br />
effects on osteoblasts [17,46]. Controversially, a recent study<br />
showed that the endogenous GC-induced signaling in osteoblasts<br />
is needed for proper <strong>bone</strong> formation in vivo in mice [47]. In vitro<br />
data regarding <strong>bone</strong> formation are also confusing, as data showing<br />
that GCs support stimulation <strong>of</strong> RANKL production, increase nodule<br />
formation, as well as inhibiting <strong>bone</strong> formation [18,20,21,48]. Our<br />
data shows that GC-mediated effects on osteoblasts in cell cultures<br />
are dependent on the ‘‘activation state’’ <strong>of</strong> the osteoblasts, with a<br />
toxic effect on non-activated cells, and a pro-osteoblastic effect<br />
on BMP-2-induced cells. This is in line with the results from the<br />
femoral heads, which decreased <strong>bone</strong> formation with PRED treatment,<br />
but increased <strong>bone</strong> formation in combination with IGF-I.<br />
The conflicting in vitro and in vivo data could indicate that we need<br />
to look more closely into GCs-mediated effects in the different<br />
functional subgroups <strong>of</strong> osteoblasts, and more <strong>important</strong>ly, how<br />
to modulate these with respect to preventing GC-induced <strong>bone</strong><br />
damage [48,49].<br />
Several studies have indicated that GCs stimulate osteoclastogenesis<br />
in vitro [50,51]; however, most <strong>of</strong> these studies were conducted<br />
in the presence <strong>of</strong> stromal/osteoblastic cells, which are<br />
known to produce RANKL in response to GCs [14,18]. We found<br />
that in pure osteoclast precursor cell cultures, GCs inhibited osteoclastogenesis<br />
by reducing the viability <strong>of</strong> the cells, which is in line<br />
with the decreased viability and osteoclast number found in PREDstimulated<br />
femoral heads. These data correlate to data showing decreased<br />
osteoclastogenesis in vivo in mice, and strongly indicate<br />
that the primary effect <strong>of</strong> GCs on osteoclastogenesis is inhibitory<br />
[15,16]. However, an interesting observation in this regard is that<br />
the effect <strong>of</strong> GCs on the mature osteoclasts, on cell viability, osteoclast<br />
number and resorption, was smaller than the effect on the differentiating<br />
osteoclasts. This could indicate that osteoclasts and<br />
their precursors have different levels <strong>of</strong> sensitivity to GC treatment.<br />
As all osteoclast cultures are a mix <strong>of</strong> mature multinucleated<br />
osteoclasts and their precursor cells, and the ratio <strong>of</strong> mature to<br />
pre-osteoclastic cells is dependent on several different aspects,<br />
such as density, donor, serum, etc. [31] we speculate that the reason<br />
for the predominantly toxic effect could be that we have more<br />
osteoclast precursors present in the cultures than Soe and Delaisse,<br />
who described a prolongation <strong>of</strong> the resorption cycle, when treating<br />
mature osteoclasts derived from CD14 + cells with PRED [52].<br />
A limitation to the study is that the effects observed with DEX<br />
and PRED have not been tested for steroids specificity with a<br />
non-GC control (e.g. estrogen or cholesterol). However, Kim et al.<br />
[17] showed that GR°C / mice were spared the impact <strong>of</strong> DEX<br />
on osteoclasts and their precursors, indicating a true GR-mediated<br />
action <strong>of</strong> DEX. This steroid specificity is furthermore supported by<br />
Battista et al. [3], which showed that the effect from DEX was<br />
dependent on the percentage <strong>of</strong> the GR in the chondrocytes. Nonetheless,<br />
future studies should include a non-GC control to ensure<br />
that the effects observed are indeed specific to the GC class <strong>of</strong><br />
steroids.<br />
In conclusions, we found that GCs did not appear to affect resting<br />
chondrocyte lifespan and function. Furthermore, GCs showed a<br />
protective effect on catabolic-induced cartilage and showed a tendency<br />
to increase cartilage formation under anabolic conditions.<br />
These results are encouraging for the use <strong>of</strong> intra-articular GC<br />
injections in OA knees. However, considering the well-established<br />
consequences on <strong>bone</strong> it is <strong>important</strong> to remember the tight functional<br />
relationship <strong>between</strong> <strong>bone</strong> and cartilage under both physiologically<br />
and pathologically conditions [27]. Thus, further studies<br />
into the functional relationship <strong>between</strong> these compartments are<br />
needed, especially with the focus on the possibility to rescue <strong>bone</strong><br />
damage by the addition <strong>of</strong> anabolic therapy, such as parathyroid<br />
hormone [48].<br />
S.H. Madsen et al. / Steroids 76 (2011) 1474–1482 1481<br />
75<br />
Acknowledgment<br />
This work was partly funded by a grant from the Danish Research<br />
Foundation, The Ministry <strong>of</strong> Science Technology and<br />
Innovation, Denmark (08-036109) with a stipend for the corresponding<br />
author.<br />
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