Involvement of the hypothalamic-pituitary-adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: Viewpoint based on a systemic pathogenetic role

Straub, Rainer H.; Cutolo, Maurizio

doi:10.1002/1529-0131(200103)44:3<493::aid-anr95>3.0.co;2-u

Cited by 198 publications

(60 citation statements)

References 106 publications

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“…In fact, the sensitization of primary afferent neurons for stimuli is a major event in arthritis (42,43). Sensitized primary afferents induce central sensitization, a major neuronal mechanism of secondary hyperalgesia (43), and they contribute to the inflammation itself through the mechanism of neurogenic inflammation (44). In mouse DRGs, we detected only SSTR1 and SSTR2A, and not SSTR3 or SSTR5, in small-and medium-diameter neurons, which suggests that the peripheral analgesic actions of pasireotide in SSTR2 -/-mice are most likely mediated via SSTR1.…”

Section: Discussionmentioning

confidence: 99%

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

Imhof¹,

Glück²,

Gajda³

et al. 2011

Arthritis & Rheumatism

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Objective. Clinical and preclinical evidence suggests that somatostatin exhibits potent antiinflammatory and antinociceptive properties. However, it is not known which of the 5 somatostatin receptor subtypes (SSTRs 1-5) is involved in these actions. The purpose of this study was to assess the effects of the stable somatostatin analogs octreotide and pasireotide (SOM230) in a mouse model of antigen-induced arthritis (AIA). Methods. Studies were performed in SSTR2-deficient mice (SSTR2 -/-) and their wild-type littermates (SSTR2 ؉/؉). The expression of SSTR1, SSTR2A, SSTR3, and SSTR5 in dorsal root ganglia was examined by immunohistochemistry.Results. Untreated SSTR2 -/-mice with AIA displayed joint swelling and mechanical hyperalgesia similar to that seen in SSTR2 ؉/؉ mice. In wild-type mice, both octreotide and pasireotide significantly attenuated knee joint swelling and histopathologic manifestations of arthritis to an extent comparable to that of dexamethasone. In SSTR2 -/-mice, the antiinflammatory effects of both octreotide and pasireotide were completely abrogated. Prolonged administration of pasireotide also inhibited joint swelling and protected against joint destruction during AIA flare reactions. In addition, both octreotide and pasireotide reduced inflammatory hyperalgesia. The antinociceptive actions of octreotide were abolished in SSTR2 -/-mice, but those of pasireotide were retained. In dorsal root ganglia of naive wild-type mice, only SSTR1 and SSTR2A, but not SSTR3 or SSTR5, were detected in a subset of small-and mediumdiameter neurons.Conclusion. Our findings indicate that the antinociceptive and antiinflammatory actions of octreotide and pasireotide are largely mediated via the SSTR2 receptor. In addition, we identified the SSTR1 receptor as a novel pharmacologic target for somatostatinmediated peripheral analgesia in inflammatory pain.

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Section: Discussionmentioning

confidence: 99%

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

Imhof¹,

Glück²,

Gajda³

et al. 2011

Arthritis & Rheumatism

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“…There is evidence that chronic inflammatory diseases such as RA are associated with changes in steroid levels, for example, DHEA (25,26). DHEA is a naturally occurring steroid for which both immunosuppressive and immunostimulatory effects have been described in vitro and in vivo (27)(28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

CYP7B expression and activity in fibroblast‐like synoviocytes from patients with rheumatoid arthritis: Regulation by proinflammatory cytokines

Dulos¹,

Vleuten²,

Kavelaars³

et al. 2005

Arthritis & Rheumatism

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Objective. The cytochrome P450 enzyme CYP7B catalyzes the conversion of dehydroepiandrosterone (DHEA) into 7␣-hydroxy-DHEA (7␣-OH-DHEA). This metabolite can stimulate the immune response. We previously reported that the severity of murine collageninduced arthritis is correlated with CYP7B messenger RNA (mRNA) expression and activity in the arthritic joint. The purpose of this study was to investigate the presence of 7␣-OH-DHEA in synovial samples and the cytokine regulation of CYP7B activity in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).Methods. The presence of 7␣-OH-DHEA was examined in synovial biopsy tissues, synovial fluid, and serum by radioimmunoassay. The effect of cytokines on CYP7B mRNA expression and CYP7B activity in FLS was examined by determining the formation of the CYP7B enzyme product 7␣-OH-DHEA with the use of high-performance liquid chromatography.Results. The CYP7B enzyme product 7␣-OH-DHEA was found in synovial biopsy tissues, synovial fluid, and serum from RA patients. The proinflammatory cytokines tumor necrosis factor ␣ (TNF␣), interleukin-1␣ (IL-1␣), IL-1␤, and IL-17 up-regulated CYP7B activity in an FLS cell line 2-10-fold. Enhanced CYP7B activity was correlated with an increase in CYP7B mRNA. The cytokine transforming growth factor ␤ inhibited CYP7B activity. Moreover, CYP7B activity was detected in 10 of 13 unstimulated synovial fibroblast cell lines. Stimulation with TNF␣ increased CYP7B activity in all cell lines tested.Conclusion. Exposure to the proinflammatory cytokines TNF␣, IL-1␣, IL-1␤, and IL-17 increases CYP7B activity in synovial tissue. Increased CYP7B activity leads to higher levels of the DHEA metabolite 7␣-OH-DHEA in synovial fluid, which may contribute to the maintenance of the chronic inflammation observed in RA patients.

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“…Findings on Sudeck's Atrophy (Reflex Sympathetic Dystrophy Syndrome) indicated that pain can be maintained by the sympathetic nervous system through a direct stimulation of nociceptive C fibers. Thus, the pain perception can be enhanced by injection of norepinephrine in patients with Sudeck's Atrophy [19]. So, it was also suspected algodystrophy-like pathogenesis for ONFH.…”

Section: Discussionmentioning

confidence: 99%

“…Since in vitro experiments already successfully demonstrated that an inflammatory response to a reduction of sympathetic nerve fibers occurs, it seems likely that the origin of the necrosis is an inflammatory action [19,20]. Straub et al [20] have shown that, number of sympathetic nerve fibers is reduced in synovial fluid of rheumatic joints [20].…”

Section: Discussionmentioning

confidence: 99%

A Animal Study of Immunohistochemical Analysis of Sympathetic Nerve Fibers in Osteonecrosis of Femoral Head in Comparison with Osteoarthritis

Yu¹

2015

MOJOR

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Involvement of the hypothalamic-pituitary-adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: Viewpoint based on a systemic pathogenetic role

Cited by 198 publications

References 106 publications

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

Differential antiinflammatory and antinociceptive effects of the somatostatin analogs octreotide and pasireotide in a mouse model of immune‐mediated arthritis

CYP7B expression and activity in fibroblast‐like synoviocytes from patients with rheumatoid arthritis: Regulation by proinflammatory cytokines

A Animal Study of Immunohistochemical Analysis of Sympathetic Nerve Fibers in Osteonecrosis of Femoral Head in Comparison with Osteoarthritis

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