Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
The Melanocortin System: A New and Important Actor on the Scene of Systemic Sclerosis.
Andersen1, Grethe N., Nagaeva2, Olga, Mincheva-Nilsson3, Lucia, Wikberg4, Jarl E.S.
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrotic destruction of the skin, vascular tree and inner organs. In SSc, the leading edge of the skin lesion is infiltrated by mononuclear cells, causing cytokine network abnormalities with increased levels of tumor necrosis factor alpha (TNFa) and the main inducer of extracellular matrix (ECM) production: transforming growth factor beta (TGFb). Due to evidence of several abnormalities in TGFb signalling, the CAT-192 study, in which patients with diffuse (d)SSc of recent onset, were treated with recombinant antibodies against human TGFb1, was initiated. As the melanocortin system plays a significant role in the regulation of TGFb and TNFa synthesis, we examined the content of messenger (m)RNA for the melanocortin receptor subtypes: MC1, 2, 3 and 5 and for the precursor protein pro-opio-melanocortin (POMC) for their natural agonist ligands (the melanocyte stimulating hormones (MSHs) and adrenocorticotroin (ACTH) in skin biopsies from the leading edge of the skin lesion in a patient with dSSc, before and after treatment with recombinant human anti-TGFb monoclonal antibodies (mAbs) as well as in skin biopsies from 3 healthy controls.
Skin biopsies, 4 mm in diameter, were achieved from the upper arm and the leading edge of the skin lesion in a recent onset dSSc patient, who participated in the CAT-192 study, before and after treatment with recombinant human anti-TGFb1 mAbs and from 3 healthy controls. The biopsies were minced, RNA extracted and examined for content of TNFa-, TGFb-, MC1-, 2-, 3-, 5- and POMC mRNA by means of quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).
In the biopsy taken from the leading edge of the skin lesion pre-treatment TNFa and TGFb levels were 4 times higher than in healthy controls, the POMC mRNA levels was similar to that found in controls. The MC1 mRNA level was slightly lower than in controls, while the MC2 and MC3 mRNA levels were immeasurable and the MC5 mRNA level low. In the biopsy taken post anti-TGFb mAbs treatment, TNFa and TGFb levels were normal. The most amazing finding was, however, an enormous rise in MC2 and MC3 mRNA levels, while MC5 mRNA increased 20-fold, POMC mRNA was considerably higher than in the pre-treatment biopsy.
Our results point at the suppression of the melanocortin system in the leading edge of the dSSc skin lesion, including suppressed expression of mRNA for the MC subtypes: 1, 2, 3 and 5 as well as of POMC mRNA. Treatment with anti-TGFb mAbs resulted in an exceptionally large increase in mRNAs for POMC, MC1, 2, 3, 5, probably a rebound effect, as TGFb is known to suppress POMC synthesis.
Melanocortin receptors are Gs-protein coupled and their activation results in a rise in intracellular cAMP, which in turn may inhibit the production of connective tissue growth factor (CTGF), a cytokine mandatory to TGFb stimulated ECM synthesis. Thus we hypothesize that the downregulation of the melanocortin system by TGFb, may further promote ECM synthesis in SSc and that the hyperpigmentation seen in SSc may be due to rebound effects in the melanocortin system in skin lesions of longer standing and decreasing TGFb concentrations.
To cite this abstract, please use the following information:
Andersen, Grethe N., Nagaeva, Olga, Mincheva-Nilsson, Lucia, Wikberg, Jarl E.S.; The Melanocortin System: A New and Important Actor on the Scene of Systemic Sclerosis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2326