Exogenous and endogenous glucocorticoids in rheumatic diseases.
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ABSTRACT: Osteocalcin is a bone-specific protein that is regularly used in the clinical setting as a serum marker of bone turnover. Recent evidence indicates that osteocalcin plays a previously unsuspected role in the control of energy metabolism. Thus, osteocalcin-deficient mice have a profoundly deranged metabolic phenotype that includes insulin resistance, glucose intolerance and abnormal fat deposition. Additionally, osteocalcin administration in mice improves insulin sensitivity and decreases fat pad mass and serum triglyceride levels. The role of osteocalcin in human macronutrient metabolism is less clear but recent studies report positive correlations between serum osteocalcin levels and established indices of metabolic health. Herein, we review key physiological functions of osteocalcin, focussing on the roles of osteocalcin in the modulation of macronutrient metabolism, male reproductive function and foetal brain development. We consider the implications of these findings for the coordination of metabolism with development and fertility. We also consider evidence that a Class C G-protein-coupled receptor from a subgroup known to mediate nutrient-sensing acts as the osteocalcin receptor.Calcified Tissue International 11/2014; 96(1). · 2.75 Impact Factor
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ABSTRACT: Glucocorticoids play a pivotal role in the management of many inflammatory rheumatic diseases. The therapeutic effects range from pain relief in arthritides, to disease-modifying effects in early rheumatoid arthritis, and to strong immunosuppressive actions in vasculitides and systemic lupus erythematosus. There are multiple indications that adverse effects are more frequent with the longer use of glucocorticoids and use of higher dosages, but high-quality data on the occurrence of adverse effects are scarce especially for dosages above 10 mg prednisone daily. The underlying rheumatic disease, disease activity, risk factors and individual responsiveness of the patient should guide treatment decisions. Monitoring for adverse effects should also be tailored to the patient. Continuously balancing the benefits and risks of glucocorticoid therapy is recommended. There is an ongoing quest for new drugs with glucocorticoid actions without the potential to cause harmful effects, such as selective glucocorticoid receptor agonists, but the application of a new compound in clinical practice will probably not occur within the next few years. In the meantime, basic research on glucocorticoid effects and detailed reports on therapeutic efficacy and occurrence of adverse effects will be valuable in weighing benefits and risks in clinical practice.Arthritis research & therapy. 01/2014; 16 Suppl 2:S2.
Article: CorticothérapieEMC - Traité de médecine AKOS. 01/2013; 8(1):1-7.
ARTHRITIS & RHEUMATISM
Vol. 63, No. 1, January 2011, pp 1–9
© 2011, American College of Rheumatology
Exogenous and Endogenous Glucocorticoids in
Frank Buttgereit,1Gerd-Ru ¨diger Burmester,2Rainer H. Straub,3Markus J. Seibel,4
and Hong Zhou5
Exogenous (i.e., therapeutic) and endogenous
(i.e., physiologic) glucocorticoids differ in several as-
pects, the most important of which are differences in
their mineralocorticoid and glucocorticoid (i.e., antiin-
flammatory) activities, respectively. Philip S. Hench first
used physiologic (but pharmaceutically manufactured)
cortisone to successfully treat a patient with rheumatoid
arthritis (RA) in 1948. Only 1 year later, however,
Hench became aware of the mineralocorticoid-related
adverse effects of cortisone, sodium/water retention and
potassium loss. As a consequence, new therapeutic
glucocorticoids were synthesized in the 1950s and 1960s.
These drugs differed from the cortisone originally de-
scribed by Hench in that they exhibited less mineralo-
corticoid activity but significantly more glucocorticoid
potencies. Examples of these drugs are the well-known
and currently used prednisone/prednisolone, methyl-
prednisolone, and the fluorinated glucocorticoids such
as dexamethasone and betamethasone. Other differ-
ences between these synthetic drugs and endogenous
glucocorticoids involve plasma kinetics, metabolism, bio-
logic half-life, lipophilicity, drug–receptor interactions,
and nongenomic potencies.
This review of the action and use of glucocorti-
coids in rheumatic disease builds on our earlier apprais-
als from 1998 and 2004 (1,2) and highlights recent
discoveries and novel insights made in the past 6 years.
We will first focus on therapeutic glucocorticoids (in-
cluding the innovative development of novel glucocorti-
coids or glucocorticoid receptor ligands) by providing an
update on their genomic, nongenomic, and clinical ac-
tions, followed by a discussion of the clinical relevance of
the timing of glucocorticoid administration. The second
part of our review will address the role of endogenous
glucocorticoids in arthritis and immunomodulation, an
area to which clinical rheumatologists and immunolo-
gists have not paid much attention in the past.
New insights into the mechanisms of genomic,
nongenomic, and clinical actions of therapeutic
The therapeutic effects of glucocorticoids are
considered to be mediated by 4 different mechanisms of
action: the classic genomic mechanism as effected by
Dr. Buttgereit’s work was supported by grants from the
Deutsche Forschungsgemeinschaft (Bu 1015/1-1, Bu 1015/4-1, and Bu
1015/7-1), the German Academy of Bone and Joint Sciences, the
University of Sydney, and the Federal Ministry of Education and
Research, Germany. Drs. Seibel and Zhou’s work was supported by
the National Health and Medical Research Council, Australia (grant
1Frank Buttgereit, MD: Charite ´ University Medicine Berlin
and Berlin-Brandenburg Center of Regenerative Therapies, Berlin,
Germany;2Gerd-Ru ¨diger Burmester, MD: Charite ´ University Medi-
cine Berlin, Berlin, Germany;
Hospital, Regensburg, Germany;
FRACP: ANZAC Research Institute, Concord Repatriation General
Hospital, and University of Sydney, Sydney, New South Wales, Aus-
University of Sydney, Sydney, New South Wales, Australia.
Dr. Buttgereit has received consulting fees and speaking fees
from Merck Serono, NitecPharma GmbH/Horizon, and Mundipharma
International (less than $10,000 each); he also has received grant
support from these companies. Dr. Straub has received consulting fees
from Merck Serono and NitecPharma GmbH/Horizon.
Address correspondence to Frank Buttgereit, MD, Depart-
ment of Rheumatology and Clinical Immunology, Charite ´ University
Medicine Berlin, Charite ´platz 1, 10117 Berlin, Germany. E-mail:
Submitted for publication March 20, 2010; accepted in revised
form September 28, 2010.
3Rainer H. Straub, MD: University
4Markus J. Seibel, MD, PhD,
5Hong Zhou, MD, PhD: ANZAC Research Institute and
Arthritis & Rheumatism
An Official Journal of the American College of Rheumatology
www.arthritisrheum.org and wileyonlinelibrary.com
activation of the cytosolic glucocorticoid receptor
(cGR); secondary nongenomic effects initiated by the
cGR; membrane-bound GR (mGR)–mediated non-
genomic effects; and nonspecific, nongenomic effects
caused by interactions with cellular membranes (3,4).
Recently, progress and new insights have been made
predominantly with regard to the classic genomic mech-
anisms and mGR-mediated nongenomic effects, as dis-
Classic genomic mechanism. The term “classic
genomic” refers to the most important mechanism of
glucocorticoid action, which involves 1) the passing of
glucocorticoid molecules through the plasma mem-
brane, 2) their high-affinity binding to the inactive cGR,
3) the formation of the activated glucocorticoid/cGR
complex and its translocation into the nucleus, and 4)
changes in gene expression via transactivation and trans-
repression. The clinical importance of this pathway has
been underlined by a recent report by Du and colleagues
(5), who described abnormalities of expression and
binding of the GR as being involved in tissue resis-
tance to glucocorticoids in patients with systemic lupus
The term “transactivation” means transcriptional
transactivation by binding of a dimerized GR protein
complex to the promoter of glucocorticoid-regulated
genes, ultimately leading to up-regulated synthesis of
certain regulatory proteins. The interference with the
activity of (proinflammatory) transcription factors (such
as activator protein 1 and NF-?B) or interferon regula-
tory factor 3 by GR monomers is called “transrepres-
sion” and leads to the down-regulation of (proinflam-
matory) protein synthesis. The underlying mechanisms
are complex and have been reviewed extensively (1–4).
It should be stressed that these processes—in contrast to
rapid nongenomic effects that occur within seconds or
minutes—require time to go into effect. At least 30
minutes pass before significant changes are recognized
in regulator protein concentrations, and it usually takes
hours or days before changes on a cell, tissue, or organ
level become evident.
An emerging concept suggests that “transrepres-
sion” is responsible for several desirable antiinflamma-
tory and immunomodulating effects, whereas “transac-
tivation” is associated with frequently occurring side
effects as well as with some immunosuppressive activi-
ties. Therefore, it has been hypothesized that selective
GR agonists (SEGRAs) addressing dimer-independent
function (i.e., transrepression) almost exclusively would
show potent glucocorticoid therapeutic activity with
reduced side effects (6–8). Indeed, the first results along
these lines seemed promising (9). However, this concept
was recently challenged by Kleiman and Tuckermann
(6), who studied a mouse knock-in strain with a
dimerization-deficient GR and demonstrated that some
inflammatory processes can be suppressed by glucocor-
ticoids while others cannot. In addition, these mice do
exhibit the classic side effects of glucocorticoids such as
Thus, depending on the process being treated,
SEGRAs could be therapeutically more or less effective
than glucocorticoids, and not all of the side effects of
glucocorticoid therapy may be reduced (6). Indeed, very
recently published data on the efficacy of ZK 245186, a
novel SEGRA, for the topical treatment of inflamma-
tory skin disease in rodent models are promising (10).
Nevertheless, from the point of view of the clinical
rheumatologist, it is discouraging to some degree that
the sound underlying theory and the promising data
reported above have not yet led to approved and wide-
spread successful clinical use of one or more of these
substances in rheumatic diseases. Therefore, it seems to
be questionable whether SEGRAs will become clinically
relevant in rheumatic diseases in the near future or even
Another interesting and recent development is
the selective amplification of glucocorticoid antiinflam-
matory activity through the synergistic multitarget ac-
tion of a combination drug, as reported by Zimmermann
et al (11). According to those investigators, the combi-
nation of prednisolone and the antithrombotic drug
dipyridamole suppressed synergistically the release of
proinflammatory cytokines and produced antiinflamma-
tory activity in acute and chronic disease (including
arthritis) models for which only a subtherapeutic dose of
prednisolone is required. They concluded that the mul-
titarget mechanism of low-dose prednisolone and dipy-
ridamole “creates a dissociated activity profile with an
increased therapeutic window through cellular network
selective amplification of glucocorticoid mediated anti-
inflammatory signaling” (11). The exact molecular
mechanism underlying the synergistic multitarget action
of these 2 drugs is, however, currently not clear.
Recently, the concept of targeted delivery of
glucocorticoids using liposomal formulations was intro-
duced, and several studies demonstrated superior effi-
cacy for water-soluble prednisolone in neutral, PEGy-
lated liposomes in animal models of RA (12–14). A
preliminary report on the first clinical use of these
formulations confirmed their potency and safety in
patients (15; see also ClinicalTrials.gov identifier:
NCT00241982). Recently, Rauchhaus et al demon-
2BUTTGEREIT ET AL
strated therapeutic efficacy and persistence of non-
PEGylated liposomal dexamethasone phosphate in
mouse collagen-induced arthritis (14). This drug shows
cellular uptake in monocytes and macrophages, is devoid
of antibody formation even after repeated administra-
tion, and accumulates in the spleen. Liposomal dexa-
methasone phosphate displayed a persistent therapeutic
effect, because a single injection of the drug at a dose of
4 mg/kg suppressed established arthritis for at least 7
days. The investigators also observed a separation be-
tween the therapeutic benefit and side effects, because
liposomal dexamethasone phosphate did not induce
hyperglycemia and led to suppression of the
hypothalamic?pituitary?adrenal (HPA) axis for a pe-
riod of time that was substantially shorter than that of
the persistent therapeutic effect (14). Rauchhaus and
colleagues attributed these improvements in the side
effect profile to a targeted, cellular delivery of the
liposomal dose form to cells and organs of the im-
mune system, mainly the spleen. They concluded that
future work should address the therapeutic persistence
in order to translate this promising development into
Membrane-bound GR–mediated nongenomic ef-
fects. Nongenomic effects of membrane-bound recep-
tors have been reported for mineralocorticoids, sex
hormones, and glucocorticoids. Membrane-bound GRs
have been detected on human peripheral blood mono-
nuclear cells (in small numbers), using highly sensitive
immunofluorescence staining with the same monoclonal
antibody as that for cGR (4). Relationships between the
number of mGR-positive monocytes and disease activity
and/or the glucocorticoid dose have been demonstrated
in patients with rheumatic diseases such as RA or
systemic lupus erythematosus (for review, see ref. 4).
More recent studies revealed the existence of membrane-
linked GRs in human T cells and provided insight into
the functional role of these receptors (16–18). It was
shown that dexamethasone rapidly inhibits the enzy-
matic activities of Lck and Fyn, leading to impaired T
cell receptor (TCR) signaling through selective targeting
of mGR (16,17). Further studies revealed that low
concentrations of dexamethasone rapidly convert the
pattern of calcium signaling by inhibiting Lck and sub-
sequently down-regulating inositol 1,4,5-trisphosphate
receptors. This weakens the strength of the TCR signal,
leading to a suppressed immune response (18).
It should be noted that nongenomic mechanisms
are also targets for the differential actions of newly
developed drugs. Very recently, compound A, a small,
nonsteroidal, plant-derived GR modulator, has been
shown to have nongenomic effects on NF-?B activation
in RA synovial fibroblasts that are different from those
of dexamethasone (19). Compound A attenuated tumor
necrosis factor ? (TNF?)–induced NF-?B activation via
attenuation of IKK phosphorylation and subsequent
I?B? degradation and attenuation of MAPK activation.
This was achieved in a GR-independent manner, but the
exact mechanism of this nongenomic effect is not clear.
The effects of compound A were, however, in sharp
contrast to the effects of dexamethasone, which was not
able to affect the respective pathways, whereas the
overall antiinflammatory effect on interleukin-1? (IL-1?)
expression was shown to be GR dependent for both
dexamethasone and compound A (19).
Clinically relevant developments. Over the past
several years, our view of glucocorticoids from a clinical
perspective has changed considerably. These drugs are
no longer seen as only providing fast relief for the signs
and symptoms of inflammation; their capability to delay
radiographic joint damage was recently shown in a
thoroughly performed meta-analysis (20). In that analy-
sis of 15 studies and 1,414 patients, the conclusion of the
authors was very clear: “Even in the most conservative
estimate, the evidence that glucocorticoids given in
addition to standard therapy can substantially reduce the
rate of erosion progression in RA is convincing.” In line
with this view are the results of a recently published
meta-analysis of 70 randomized placebo- or drug-
controlled studies including 112 comparisons (21). The
authors of that report observed similar effects of
disease-modifying antirheumatic drugs, glucocorticoids,
and biologic agents on radiographic progression in RA.
Clinical progress was also recently made by the
formulation of recommendations regarding which ad-
verse events of glucocorticoid treatment in RA should
be monitored, how to monitor them, and at what fre-
quency (22). As the key message, 2 levels of monitoring
adverse events of glucocorticoid treatment in RA were
proposed. First, for daily practice, details regarding how
to identify adverse events in a feasible manner were
provided. This should result in preventive and therapeu-
tic measures to minimize the risks of glucocorticoid
therapy. Second, for clinical trials in the future, recom-
mendations were made regarding how to assess accu-
rately the frequency and severity of a larger set of
Timing of glucocorticoid administration
The circadian rhythm of pain, stiffness, and func-
tional disability as well as the underlying cyclic variations
GLUCOCORTICOIDS IN RHEUMATIC DISEASES3
in hormone levels and cytokine concentrations is a
well-known phenomenon in patients with RA (23).
Similar diurnal variations have been described for other
rheumatic diseases such as polymyalgia rheumatica and
ankylosing spondylitis. Although data for the latter
conditions are scarce, detailed data for RA have accu-
mulated. In RA, major signs and symptoms such as pain,
inflammation, and stiffness vary as a function of the time
of day, usually with the greatest severity of symptoms
occurring in the morning hours.
In RA, pain, inflammation, and stiffness are
preceded by elevated levels of IL-6, TNF, and other
proinflammatory cytokines (23–29), and a causal—not
only a temporal—relationship has been suggested for
the following reasons. The pathogenesis of RA involves
complex humoral and cellular reactions including im-
mune complex formation, vascular reactions, and infil-
tration of lymphocytes and monocytes into the synovium
(30). Humoral factors such as interferon, cytokines
(especially TNF?, IL-6, IL-10, IL-15, IL-18, and IL-1
receptor antagonist), growth factors, colony-stimulating
factors, and chemotactic factors are released by a variety
of cells and perpetuate inflammation and destruction.
Of central importance is the fact that IL-6 is the
most abundant cytokine in the serum and synovial fluid
of patients with RA, mediating both systemic (acute-
phase response, anemia, thrombocytosis, fatigue, osteo-
porosis) and articular symptoms. It has been shown that
levels of IL-6 and its soluble receptor in synovial fluid
correlate significantly with both local joint measures of
chronic synovitis and the severity of joint destruction in
patients with RA. IL-6 facilitates the recruitment and
enhances the activity of neutrophils, monocytes, endo-
thelial cells, and bone-derived cells. IL-6 has also been
assigned an important role in the pathophysiology of
arthritis pain (31). Finally, inflammatory edema of the
synovium and the periarticular structures interferes with
joint biomechanics and may contribute, together with
the redistribution of interstitial fluids during sleep and
circadian changes in synovial fluid composition, to joint
stiffness that is most pronounced in the morning (32).
Based on these considerations and given that
IL-6, other humoral factors (e.g., TNF?), as well as
cellular reactions (e.g., leukocyte traffic and access of
leukocytes to the site of inflammation) involved in
RA pathogenesis can be targeted with glucocorticoids
(1,2), the hypothesis was derived that improving the
timing of glucocorticoid administration may help to
optimize therapy for RA. The scientific basis for this
hypothesis was provided by the following 4 lines of
reasoning. First, pain, fatigue, morning stiffness, and
immobility are the common symptoms affecting patient
quality of life and the ability to stay gainfully employed
(33). Second, the increase in the levels of IL-6 and other
proinflammatory cytokines that occurs overnight is
thought to initiate a cascade of events promoting the
severity of these symptoms. Third, preventing the noc-
turnal rise in the levels of proinflammatory cytokines
should be more effective than treating established symp-
toms. Fourth, glucocorticoids also have profound effects
on cellular immunity; therefore, given the existence of
cellular circadian rhythms, preventing up-regulation of
immune cell activity (including traffic) could be more
effective than reducing established cellular activity af-
terward. From this point of view, the administration of
glucocorticoids between 6:00 AM and 8:00 AM may not be
optimal (Figure 1A).
Administering a standard glucocorticoid drug
prior to the flare of cytokine synthesis and inflammatory
activity would necessitate waking the patient each night,
which clearly is not a feasible option. Therefore, a newly
developed modified-release prednisone tablet releases
prednisone 4 hours after ingestion, i.e., at approximately
2:00 AM if it is taken at bedtime. This novel medication
was investigated in the CAPRA-1 study, which consisted
of an initial 3-month double-blind phase followed by a
9-month open-label extension phase (23).
The new formulation was shown to be clinically
superior to the conventional immediate-release prepa-
ration with respect to reducing morning joint stiffness
(Figure 1B). This beneficial effect was noted in addition
to clinical control of the disease resulting from treat-
ment with conventional prednisone. The expression of
IL-6 was also decreased by modified-release prednisone
but remained unchanged by immediate-release pred-
nisone. The safety profile did not show differences
between the 2 preparations (23).
After 12 months of treatment (i.e., at the end of
the open-label phase), the duration of morning stiffness
was reduced by ?50% in patients treated with modified-
release prednisone, and 37% of these patients achieved
improvement according to the American College of
Rheumatology criteria for 20% improvement in disease
activity (34,35). As part of the CAPRA1 study,
corticotropin-releasing hormone tests were performed
in a subgroup of patients; no differences were seen
between modified-release prednisone and standard
prednisone with regard to the influence on the HPA axis
(36). Taken together, these data support the view that
optimizing the timing of glucocorticoid administration
with modified-release prednisone improves the risk/
4 BUTTGEREIT ET AL
benefit ratio of long-term low-dose glucocorticoid treat-
ment in patients with RA.
The role of endogenous glucocorticoids in
The above-described actions of exogenous glu-
cocorticoids in the systemic treatment of RA and other
inflammatory diseases are well established. In contrast,
the role of endogenous glucocorticoids in and their
contribution to the susceptibility and severity of arthritis
remains inconclusive. Although the historic dogma stip-
ulated that glucocorticoid actions on target tissues are
determined by glucocorticoid plasma concentrations and
the tissue-specific density of GRs only, new insights into
the mechanisms of glucocorticoid action suggest that
endogenous glucocorticoids are subject to extensive
prereceptor metabolism. Within target cells or tissues,
the action of glucocorticoids depends not only on the
plasma hormone level, receptor expression, and
receptor–effector coupling, but also on local glucocorti-
coid metabolism. Specifically, the 11?-hydroxysteroid
dehydrogenases (11?-HSDs) appear to govern access of
glucocorticoids to their cognate receptors by changing
the balance between active and inactive glucocorticoids
within the cell (37,38). Thus, 11?-HSD type 1 (11?-
HSD1), through its predominant reductase activity, ca-
talyses the formation of bioactive cortisol (in humans)
and corticosterone (in rodents) from inactive cortisone
and 11-dehydrocorticosterone, respectively. This
NADP-positive hydrogen-dependent enzyme is present
in many tissues and usually increases the intracellular
availability of active glucocorticoids. In contrast, 11?-
HSD2 possesses dehydrogenase activity only, inactivates
active glucocorticoids, and thus decreases the concentra-
tion of bioactive glucocorticoids in the cell (38).
Proinflammatory cytokines such as IL-1? and
TNF? have been shown to stimulate 11?-HSD1 and
down-regulate 11?-HSD2 expression (39). Hence, spe-
Figure 1. Effects of conventional immediate-release prednisone versus modified-release pred-
nisone on interleukin-6 (IL-6) levels and clinical symptoms in patients with rheumatoid arthritis. A,
Administration of glucocorticoids between 6:00 AM and 8:00 AM may not be optimal, because the
overnight rise in the level of IL-6 has already triggered irritation and swelling of the synovia, leading
to joint pain, joint stiffness, fatigue, and immobility that is pronounced in the morning. B, Use of
modified-release prednisone in order to prevent the level of IL-6 from increasing at night was
recently shown to be clinically and significantly better than use of the conventional immediate-
release preparation with respect to reducing morning joint stiffness. MMP ? matrix metallopro-
teinase; VEGF ? vascular endothelial growth factor. Color figure can be viewed in the online issue,
which is available at http://onlinelibrary.wiley.com/journal/10.1002(ISSN)1529-0131.
GLUCOCORTICOIDS IN RHEUMATIC DISEASES5
cific proinflammatory cytokines are able to modulate
local intracellular glucocorticoid metabolism, potentially
modifying their own proinflammatory effects. Recently,
Hardy and colleagues confirmed the existence of sub-
stantial glucocorticoid metabolism in the joint by dem-
onstrating that TNF? and IL-1? cause a dramatic induc-
tion of 11?-HSD1 activity in primary cultures of synovial
fibroblasts isolated from synovial tissue biopsy speci-
mens obtained from patients with RA (40). Further-
more, in patients with RA, 11?-HSD1 activity in synovial
tissue explants strongly correlated with measures of
systemic inflammation, suggesting that synovial glu-
cocorticoid production through 11?-HSD1 enzyme ac-
tivity is influenced by local inflammation.
Using a rodent model of immune-mediated ar-
thritis, we recently observed that targeted disruption of
glucocorticoid signaling in osteoblasts strongly attenu-
ated joint inflammation and cartilage destruction (41).
Specifically, K/BxN mouse serum–induced autoimmune
arthritis (42,43) was initiated in a transgenic mouse in
which the expression of 11?-HSD2 had been targeted
exclusively to osteoblasts using the 2.3-kb collagen ?1(I)
promoter (Col2.3–11?-HSD2–transgenic mice) (44,45).
This transgene is expressed in mature osteoblasts and
osteocytes only, with no expression in cartilage, synovio-
cytes, or, in fact, any other tissue. Therefore, overexpres-
sion of 11?-HSD2 via the Col2.3 promoter is a specific
and highly effective way of abolishing glucocorticoid
signaling in osteoblasts and osteocytes only.
As shown in Figure 2, acute arthritis developed in
both transgenic and wild-type mice treated with K/BxN
mouse serum. However, during the ensuing subacute
phase, both joint inflammation activity and cartilage
destruction were significantly attenuated in transgenic
mice, as judged by clinical and histologic analyses. Bone
turnover and bone volume were unchanged in arthritic
transgenic mice, while the corresponding wild-type mice
exhibited accelerated bone resorption, suppressed os-
teoblast activity, and reduced bone volume, compatible
with the known effects of active inflammation on bone
(41). Although these results were somewhat unexpected,
they clearly support the concept that local endogenous
glucocorticoids play an important, proinflammatory role
in immune arthritis.
Of note, the course of acute arthritis was similar
in transgenic and wild-type mice until ?5–6 days postin-
duction. This observation indicates that disruption of
osteoblastic glucocorticoid signaling does not affect the
acute phase of arthritis. Hence, the acute and post-acute
stages of immune-mediated arthritis may be regulated by
different mechanisms, at least in the model of KBxN
Figure 2. Inflammation and tibiotalar joint damage in hydroxysteroid
dehydrogenase type 2 (HSD2)–transgenic (TG) wild-type (WT) mice.
Arthritis was induced by injection of K/BxN mouse serum; nonarthritic
control (CTR) mice were injected with phosphate buffered saline/
normal saline. A, Estimated marginal mean (EMM) values for ankle
size from day 1 to day 14. B–D, Clinical appearance of ankle joints.
E–G, Hematoxylin and eosin staining of ankle joints. Arrows show
synovial inflammation and soft tissue edema. Bars ? 500 ?m. H–J,
Toluidine blue staining of ankle joints. Arrows show proteoglycan loss
of articular cartilage. Bars ? 100 ?m. K, Histopathology scores in
arthritic K/BxN mice 14 days postinjection. Both inflammatory activity
and cartilage damage were less pronounced in HSD2-transgenic mice
than in WT mice treated with K/BxN mouse serum. Bars show the
mean ? SD. NS ? not significant.
6 BUTTGEREIT ET AL
mouse serum–induced arthritis. This strongly suggests
that osteoblasts, under the control of endogenous glu-
cocorticoids, modulate immune-mediated inflammatory
responses and, as a consequence, inflammation-induced
cartilage damage and bone integrity. These findings are
supported by recent observations suggesting that the
effects of glucocorticoids follow a dose–response curve,
with permissive or even stimulatory effects at physio-
logic concentrations and suppressive effects at pharma-
cologic concentrations (46) (Figure 3).
Immunostimulatory effect of glucocorticoids
Between 1940 and the 1980s, as the effects of
cortisol on bodily functions were revealed, it was thought
that an initial cortisol surge serves to stimulate defense
mechanisms that included the first attack to the immune
system (for review, see ref. 46). Since publication of
the study by Munck and Guyre in 1986 until 1995, the
pendulum swung to the opposite side, and it was cor-
rectly realized that cortisol has prominent immunosup-
pressive effects (47,48). Generally, most of these studies
were carried out using relatively high doses of immuno-
suppressive cortisol equivalents. This immunosuppressive
concept was also confirmed by studies in patients with
RA who were being treated with glucocorticoids (2).
In the 2 last decades, the immunomodulating role
of cortisol has been critically reexamined, because sev-
eral in vitro and in vivo studies demonstrated immuno-
stimulating effects of cortisol in both humans and ro-
dents (Figure 3). For example, pokeweed mitogen–
stimulated IgG synthesis by human peripheral blood
mononuclear cells was increased by prednisolone (49).
Corticosterone (the equivalent of cortisol in rodents)
increased anti-TCR–stimulated rat splenic lymphocyte
mitogenesis (50). Kinetics experiments showed that cor-
ticosterone had to be present within 60 minutes after the
initiation of TCR activation to produce maximal enhanc-
ing effects; a delay of ?2 hours rendered corticosterone
ineffective (50). Corticosterone potently enhanced a
TCR-induced increase in CD4 surface expression in
vitro (51), which was dependent on the timing of admin-
istration and cell density.
Glucocorticoids enhanced nitric oxide and IL-1?
secretion by rat alveolar macrophages (52). Alveolar
macrophages from glucocorticoid-treated rats were
highly sensitive to lipopolysaccharide (LPS) and re-
leased large amounts of TNF ex vivo (53). A very similar
relationship between prior cortisol infusion and subse-
quent LPS-stimulated levels of IL-6 and TNF was de-
scribed in humans (54). In those experiments, intrave-
nous LPS administration was followed by significant
elevations in body temperature, pulse rate, and plasma
epinephrine, serum C-reactive protein (CRP), serum
TNF, and serum IL-6 levels (54). Glucocorticoids, when
given immediately before and concomitantly with LPS,
significantly attenuated the response of body tempera-
ture, pulse rate, and plasma epinephrine, serum CRP,
and TNF levels, while the IL-6 response was unchanged
(54). Surprisingly, patients who received LPS 12 or 144
hours after cortisol infusion displayed hemodynamic and
hormonal responses similar to those in patients who
received LPS alone, but their circulating levels of both
IL-6 and TNF were greater than those observed in
patients who received LPS alone (54).
Another study used freshly prepared human peri-
pheral blood leukocytes incubated with bacterial culture
suspensions, either with or without fixed human immu-
noglobulins, in the presence of increasing concentrations
of cortisol (55). The immunosuppressive activities nor-
mally caused by cortisol were partially antagonized,
leading to increased TNF and granulocyte–macrophage
colony-stimulating factor secretion, whereas the expres-
sion of IL-10 was diminished. However, this effect could
be reversed with increasing concentrations of cortisol
(55), which indicates that the concentration of glucocor-
ticoids plays an important role. Indeed, a recent study
showed that low levels of corticosterone enhanced the
nitric oxide production as well as messenger RNA
expression of the proinflammatory cytokines, chemo-
Figure 3. Spectrum of cortisol effects: dose–response curve for corti-
sol or dexamethasone and immune response (immunosuppression
versus immunostimulation). The optimum point (OP) is the typical
situation under normal conditions (cortisol in serum). Higher doses
would lead to immunosuppression, and lower doses would lead to
GLUCOCORTICOIDS IN RHEUMATIC DISEASES7
kines, and enzymes required for mediator synthesis (56),
while high levels of corticosterone strongly repressed
macrophage function; these effects were mediated by
the classic GR.
In addition, it is known that some important
proinflammatory molecules are directly stimulated by
glucocorticoids; among these, glucocorticoid-induced
TNF receptor (GITR) protein is the best example. GITR
protein is expressed in several cells and tissues, including
T cells and natural killer cells, and it is involved in the
activation of both acquired and innate immunity (57).
The stimulating influence of glucocorticoids on
leukocyte redistribution is probably the most important
factor in terms of supporting immune responses (58,59).
It has been repeatedly demonstrated that cortisol surges
lead to increased leukocyte mobilization that is an
important prerequisite for leukocyte entry into inflamed
tissue (60). This glucocorticoid increase on a systemic
level in the circulation can be a proinflammatory event.
In conclusion, several independent mechanisms
of action demonstrate the immunosupportive effect of
glucocorticoids. The concentration of glucocorticoids
and the timing of administration are decisive (Figure 3).
These facts must be considered when evaluating the
therapeutic potential of modifying the metabolism of
Therapeutic glucocorticoids are still among the
most important drugs in rheumatic diseases because of
their clinically important antiinflammatory and immu-
nosuppressive effects. However, glucocorticoids, espe-
cially at higher doses and with long-term use, have
pleiotropic effects causing several adverse reactions that
limit their use. Therefore, it is not surprising that
intensive basic and clinical research is currently under
way to improve the risk/benefit ratio of these drugs,
using several different approaches. Of note, investigat-
ing the effects and therapeutic potential of endogenous
glucocorticoids is also within the focus of this research.
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published.
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