Comparative enzymology of 11β-hydroxysteroid dehydrogenase type 1 from six speciesEver since the first use of cortisone, glucocorticoids have had a controversial role in the treatment of RA. There has been equally controversial research into the possible involvement of endogenous glucocorticoids, and their secretion beta-htdroxysteroid the hypothalamic—pituitary—adrenal HPA axis, in the development and persistence glucocorticlid inflammatory arthritis. Recently, our understanding of how glucocorticoids act has expanded substantially with the characterization of glucocorticoid-metabolizing enzymes that regulate glucocorticoid action at tissue level. Without these enzymes, cortisone and prednisone would be therapeutically useless. Furthermore, in normal individuals, 11 beta-hydroxysteroid dehydrogenases changing glucocorticoid action activities of these enzymes influence the function of other components of the Adblock vs adblock plus axis.
Comparative enzymology of 11β-hydroxysteroid dehydrogenase type 1 from six species
Ever since the first use of cortisone, glucocorticoids have had a controversial role in the treatment of RA. There has been equally controversial research into the possible involvement of endogenous glucocorticoids, and their secretion via the hypothalamic—pituitary—adrenal HPA axis, in the development and persistence of inflammatory arthritis.
Recently, our understanding of how glucocorticoids act has expanded substantially with the characterization of glucocorticoid-metabolizing enzymes that regulate glucocorticoid action at tissue level.
Without these enzymes, cortisone and prednisone would be therapeutically useless. Furthermore, in normal individuals, the activities of these enzymes influence the function of other components of the HPA axis. These enzymes are expressed in human synovial tissue and bone and have been implicated in the control of synovial inflammation, the development of periarticular bone loss and the sensitivity of bone to therapeutic glucocorticoids. This article reviews recent findings in this area that highlight the role of these enzymes in rheumatic diseases.
Ever since the first use of cortisone, therapeutic glucocorticoids have been widely used to treat RA though their appropriate place in disease management remains the subject of much debate.
There has also been extensive research into the possible dysregulation of endogenous glucocorticoids and their secretion via the hypothalamic—pituitary—adrenal HPA axis, and the role of this in the development and persistence of inflammatory arthritis.
On the basis of the initial success of cortisone in the treatment of inflammatory arthritis, it was postulated that patients with RA had a defect in the amount or effectiveness of endogenously generated glucocorticoids [ 1 , 2 ]. This view was given great support by experiments with animal models, which demonstrated that related histocompatible strains of rats had markedly different sensitivities to the induction of chronic experimental arthritis. The defect in the arthritis-prone rats was linked to a failure of the HPA axis to increase glucocorticoid output in response to an inflammatory insult [ 3 ].
The administration of the glucocorticoid receptor antagonist RU, a drug that blocks glucocorticoid action within tissues, rendered arthritis-resistant rats more susceptible to experimental arthritis, and the administration of the synthetic glucocorticoid dexamethasone to arthritis-prone animals rendered them resistant.
These findings stimulated a search for a similar defect in humans. However, such a defect has been difficult to find. Patients with established RA who have not previously received therapeutic glucocorticoids have no consistent clinical or biochemical evidence of adrenal insufficiency when standard endocrine tests are used [ 4 ].
The circulating levels of cortisol the main endogenous glucocorticoid in humans in RA patients appear remarkably similar to, if not higher than, those of healthy subjects [ 5 , 6 ].
The possibility of a subtle defect in cortisol secretion has been raised on the basis of an impaired maximal adrenal response to the insulin tolerance test [ 6 ]. However, in normal individuals, an inflammatory insult is a stimulus for the HPA axis, and in patients with RA there may be relative corticosteroid insufficiency, with normal levels of cortisol in the circulation actually being inappropriately low for the degree of inflammatory stress [ 7 ]. The major endpoint of these experiments was generally the level of cortisol in the circulation.
However, it is now clear that the HPA axis extends into the tissues and is influenced by changes occurring at this level. The HPA axis controls the secretion of cortisol from the adrenal glands.
Corticotrophin-releasing hormone CRH , released from the hypothalamus, stimulates the release of adrenocorticotropic hormone ACTH by the anterior pituitary gland, which in turn, stimulates the secretion of cortisol. CRH secretion, with its characteristic diurnal rhythm, is regulated by stress and inflammatory cytokines and is inhibited by negative feedback from cortisol itself [ 8 ].
Historically, it has been inferred that the level of cortisol in the circulation is an accurate indicator of the amount of action that cortisol will have in the tissues. It is now clear that this is incorrect in several respects [ 8 ] Fig. Cortisol bound to CBG cannot normally diffuse out of the intravascular space, so the level of cortisol measured in the circulation is vastly higher than the level in interstitial fluid.
A further complicating factor is that CBG levels decrease during inflammation through reduced synthesis and cleavage by neutrophil elastase [ 10 ].
Additionally, an increase in endothelial permeability resulting from inflammation can allow CBG-bound cortisol to enter the interstitial fluid. Even if bioavailable cortisol levels in the tissues could be measured accurately, there are multiple levels within the cell that potentially regulate the action of cortisol [ 11 , 12 ].
These include the number and binding affinity of the glucocorticoid receptor. In addition, post-receptor mechanisms regulate glucocorticoid action within the cell. Perhaps of most significance, it is now known that there is extensive metabolism of glucocorticoids in a range of tissues [ 13 ]. This metabolism has local consequences for the individual tissues as discussed below and also affects the HPA axis through both catabolism and regeneration of active glucocorticoid Fig. The level of cortisol within the circulation, therefore, cannot be assumed to be equivalent to that acting in the tissue.
Furthermore, tissue metabolism of synthetic glucocorticoids can be different from that of endogenous glucocorticoids. This needs to be taken into account when trying to understand the action of various glucocorticoids on a tissue or disease process and is likely to explain certain clinical observations made with therapeutic glucocorticoids.
Schematic illustration of the various levels at which glucocorticoid action can be regulated. Contemporary view of the HPA axis. The level of cortisol in the circulation is regulated by the production of ACTH from the pituitary but the level of cortisol is also impacted upon by peripheral metabolism of cortisol and cortisone. The importance of tissue metabolism is illustrated by the finding that glucocorticoids such as cortisone or prednisone do not bind to or activate the glucocorticoid receptor to any great extent [ 14 ].
These enzymes interconvert hormonally inactive cortisone with hormonally active cortisol cortisol is referred to as hydrocortisone when given therapeutically; Fig.
They also interconvert inactive prednisone with active prednisolone. These individuals are unresponsive to high-dose cortisone acetate or prednisone, but maintain sensitivity to hydrocortisone i. The kidney is, thus, the principle site of generation of cortisone within the body with smaller contributions being made by other mineralocorticoid target tissues colon, pancreas and salivary glands.
Although termed the Syndrome of Apparent Mineralocorticoid Excess, it is now known that cortisol itself is acting as the excess mineralocorticoid in these patients [ 18 ]. This condition is diagnosed on the basis of the absence of cortisone metabolites in the urine. It is now clear that the cyclical inactivation and reactivation of cortisol has an impact on the HPA axis and thus cortisol secretion [ 13 ].
This can result in adrenal hyperplasia with excessive adrenal androgen production. Several decades ago it was established that synovial tissue explants from patients with RA could interconvert cortisone and cortisol [ 20 , 21 ]. It was also observed that cortisone and cortisol could be interconverted when injected into the joint [ 1 ].
However, these experiments were performed before the enzymes responsible for these reactions had been characterized. These early findings of glucocorticoid metabolism in synovial tissue have now been extended by several groups and the results summarized schematically in Fig. A reduction in local activity of the sympathetic nervous system in RA as opposed to OA synovium, a consequence of loss of sympathetic nerve fibres, was considered to be the basis for this change in local steroid metabolism in RA.
Loss of sympathetic activity would thus be expected to augment cortisol inactivation or cortisol to cortisone conversion. Corticosteroid metabolism in synovial tissue and the cells that mediate this. Various cell types present within the synovium have the capacity to metabolize corticosteroids and metabolism can lead to either activation or inactivation. A similar analysis of synovial tissue was carried out by Hardy et al.
These data and those of Schmidt et al. Analysis of SF corticosteroid concentrations in RA suggested that there was, however, a net glucocorticoid-activating capacity within the joint. Additional work has been carried out on primary cultures of synovial fibroblasts derived from patients with RA or OA [ 27 ]. On the basis of these studies, it is likely that the level of active glucocorticoid within the rheumatoid joint is higher than that in the general circulation.
This appears to be a consequence of net glucocorticoid activation within the synovium. This probably explains why long-term oral use of these drugs is associated with greater adverse effects on skin and fat tissue relative to prednisone for the same degree of suppression of inflammation [ 29 ]. In the same way that defects in the HPA axis have been proposed to play a role in RA development and progression, abnormal glucocorticoid metabolism in the tissue in response to inflammation is equally likely to be important.
Glucocorticoid metabolism has only been studied cross-sectionally in patients with established RA so longitudinal studies in patients at an earlier stage of disease will be required to address these questions.
In addition, differences in glucocorticoid metabolism may impact on individual responsiveness to glucocorticoid therapy. One of the earliest recognized adverse effects of long-term therapeutic glucocorticoid use was the development of fractures. The mechanisms by which glucocorticoids have a detrimental effect on bone are complex and poorly understood [ 11 ]. However, it is generally recognized that excess glucocorticoids primarily affect the function of osteoblasts.
The capacity of bone itself to metabolize glucocorticoids has recently been explored. Chips of human bone, obtained at orthopaedic surgery, were shown to interconvert cortisone and cortisol [ 33 ]. Activity is low in immature osteoblasts but increases at a time coincident with the expression of specific markers of the osteoblast phenotype [ 34 ].
It has been shown that the local generation of glucocorticoids by osteoblasts is an important mechanism for the induction of differentiation of these cells. Enzyme expression slows cellular proliferation and enhances differentiation [ 30 ]. Enzyme activity in osteoblasts is also increased by pro-inflammatory cytokines with glucocorticoids themselves having a synergistic effect; phenomena similar to those seen in synovial fibroblasts [ 28 , 35 , 36 ].
These changes with pro-inflammatory cytokines suggest that the local exposure of bone, or more specifically osteoblasts, to active glucocorticoids will increase substantially during inflammation through the induction of local glucocorticoid activation.
Such a sensitization of bone has been hypothesized to contribute to the development of periarticular osteopenia and systemic osteoporosis in inflammatory arthritis [ 35 ]. Osteoblasts from patients in the seventh and eighth decades of life generated several times more cortisol than osteoblasts from younger donors in their second and third decades. Such an increase raises the possibility that bone tissue in an elderly individual will be exposed to a substantially higher level of active glucocorticoid than that of a younger individual, even though the level of active glucocorticoid in the circulation changes little.
Thus, in addition to oestrogen deficiency, skeletal ageing might also be due to local glucocorticoid excess. A significant negative correlation was observed between the level of circulating cortisone and serum OC, a relationship independent of the circulating level of cortisol. This is supported by a study in healthy individuals that examined the determinants of bone sensitivity to prednisolone treatment [ 39 ].
These changes occurred independently of the circulating level of glucocorticoid. Given that both synovial tissue and bone have the capacity to metabolize glucocorticoids, it is possible that metabolism in one tissue will affect the function of the other. It is also possible that glucocorticoid metabolism in bone could impact on synovial pathology.
It was found that using this experimental strategy to block glucocorticoid signalling in osteoblasts reduced the extent of arthritis. The mechanism underlying this glucocorticoid-dependent anti-inflammatory action is currently being explored.
These studies suggest that the interaction between synovium and bone in their metabolism of glucocorticoids are likely to be bidirectional and complex.
The presence of glucocorticoid-metabolizing enzymes in both synovium and bone needs to be considered when interpreting the effect of endogenous and exogenous glucocorticoids on these tissues. The strong induction of glucocorticoid activation in the synovium in the presence of inflammation suggests that this may be a natural anti-inflammatory mechanism but when it continues in the presence of long-term inflammation there are likely to be detrimental consequences, particularly on adjacent bone tissue.
The extent of glucocorticoid activation correlates with the sensitivity of bone to glucocorticoids. It remains to be determined whether local glucocorticoid metabolism influences the development or the clinical expression of synovial inflammation. On the basis of the studies described in this review, it would be predicted that these drugs would have a useful role in age-related bone loss, but there would be a risk of exacerbating synovial inflammation in patients with RA.
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