To the Editor:

We read the report by Makrygiannakis et al (1), on the effects of intraarticular corticosteroids on bone biology regulation, with great interest, since it may have major consequences regarding the development of novel treatment concepts in rheumatoid arthritis (RA). In Makrygiannakis and colleagues' study, evaluation of RANKL, osteoprotegerin (OPG), and surface marker expression in synovium of arthritis patients or in human osteoblast-like cells showed that a decrease in inflammation is accompanied by down-modulation of markers of bone destruction. These findings offer a rationale for the beneficial effect of corticosteroids on joint erosion in arthritis.

Interestingly, treatment of osteoblast-like cells with glucocorticoids (GCs) promoted osteoclastogenesis by inhibiting OPG and increasing RANKL expression. However, following priming with tumor necrosis factor α (TNFα), a condition that mimics the proinflammatory milieu of the rheumatoid joint, GCs decreased RANKL expression. These findings imply that GCs affect bone biology differently in the presence and in the absence of inflammation mediators and may indicate why GC treatment has bone-conserving potential in RA even though it induces osteoporosis in the spine (bone not affected by RA and thereby not surrounded by inflammation mediators).

As a consequence, there is a need for treatment strategies that more specifically target inflamed tissues and thereby circumvent the undesired effects of GCs (2). One such strategy is the tissue targeting of GCs with liposomes. Liposomes loaded with GCs can be designed to target certain cell types or tissue and thereby may help to further improve the clinical efficacy of GC therapy (3).

Alternatively, a novel mechanism that has attracted attention mainly for its dramatic impact on the development of obesity and metabolic syndrome could offer a promising avenue for new small-molecule drugs to exploit desired GC effects in a tissue-specific manner. Types 1 and 2 11β-hydroxysteroid dehydrogenases (11β-OHSD), coined the “cortisone/cortisol shuttle,” control local concentrations of cortisol, the main active GC in humans. The shuttle is present at sites of inflammation (ref.4 and Volkmann A, Wilckens T: unpublished observations) and also in bone (5). It is intriguing that patients with early RA show transient expression of the catabolizing enzyme in monocytes during the first 2 years of disease (6).

Cooper et al (7) observed that activation of cortisone to cortisol by 11β-OHSD1 in osteoblasts appears to be increased by exposure to inflammation mediators such as TNFα. They concluded that enhanced local cortisol synthesis could be causally linked to the bone destruction observed in RA. However, the data presented by Makrygiannakis et al (1) rather imply that there is a tight local control mechanism that prevents bone destruction during an inflammatory reaction: TNFα reversed the effect of GCs, leading to down-regulation of RANKL expression in osteoblasts, which would result in protection against bone destruction in vivo. In this scenario, endogenous GCs such as cortisol are necessary for bone protection in arthritis. Indeed, preliminary evidence suggests that an inhibitor of endogenous GC metabolism inhibits adjuvant- and pristane-induced arthritis, even if the treatment is discontinued during ongoing disease (8).

In summary, we propose that targeting local, tissue-specific GC metabolism offers a promising approach to the treatment of inflammatory diseases associated with bone destruction, such as RA. The findings reported by Makrygiannakis and colleagues warrant further studies on the complex interaction between GCs and bone. It is now also accepted that GCs are essential components of normal bone formation and remodeling (5), and they therefore offer a variety of avenues for development of targeted therapies in order to conserve bone physiology. The recently established link between 11β-OHSD2 and the pathogenesis of RA (9) further corroborates our proposed concept for the therapeutic action of GCs and indicates that 11β-OHSD2 may be a novel therapeutic target.


Dr. Wilckens owns stock in BioNetWorks, is the inventor on patents filed by BioNetWorks, and receives royalties for hydroxysteroid dehydrogenase inhibitors developed by BioNetWorks. Dr. Volkmann owns stock in BioNetWorks.

Thomas Wilckens MD*, Ariane Volkmann PhD*, * BioNetWorks GmbH, Munich, Germany.