Background Relaxin (RLX) is a small dimeric hormone, with similar structure to insulin. It is involved in extracellular matrix remodeling and plays anti-fibrotic role in lung, liver, kidney and heart, promoting also wound healing (1). Recombinant human relaxin (RH-RLX) has been used to attenuate skin fibrosis and reducing functional disability in systemic sclerosis (SSc) patients: but the results remained controversial (2).
Objectives To investigate the ineffectiveness of RH-RLX treatment in SSc by analyzing serum RLX levels, tissue/cellular expression of RLX receptor RXFP1/LGR7 and the relative mRNA levels in patients with limited-(lSSc) and diffuse-(dSSc) SSc and in healthy controls.
Methods 10 lSSc-patients, 10 dSSc-patients and 10 controls were enrolled. RLX serum levels were assayed by ELISA. RLX receptor RXFP1/LGR7 was evaluated by immunohistochemistry on skin biopsies from patients with dSSc, lSSc (affected and not-affected skin) and controls. RXFP1/LGR7 mRNA (quantitative-real-time-PCR) levels were determined in SSc-dermal-fibroblasts and in control-dermal-fibroblasts cultured from passage 1 to passage 10.
Results Serum RLX appeared to be significantly higher in SSc patients (both lSSc and dSSc) compared to controls (p<0.001). Enhanced RXFP1/LGR7 immunoreactivity was found in keratinocytes, fibroblasts, endothelium, sebaceous/sweat-glands from control skin and not-affected skin of lSSc-patients. No RXFP1/LGR7 immunoreactivity was found in lSSc/dSSc affected skin. RXFP1/LGR7 mRNA levels were 8 times higher in dSSc/lSSc-affected fibroblasts compared to lSSc unaffected and control fibroblasts (p<0.01). Moreover, RXFP1/LGR7 mRNA levels statistically increased from passage 1 to passage 10 in dSSc/lSSc-affected fibroblasts (p<0.01), while remained constant in lSSc unaffected and control fibroblasts. Finally, despite high RXFP1/LGR7 mRNA levels were found in dSSc/lSSc-affected fibroblasts, the RXFP1/LGR7 protein was always lacking.
Conclusions These results suggest that the ineffectiveness of RLX treatment to manage SSc dermal fibrosis could be due to primary alterations of RXFP1/LGR7 receptor in the lesional skin of SSc patients. Moreover, the above mentioned alterations could be the cause of higher circulating serum RLX levels in SSc patients. Therefore, the novel therapeutic strategies based on the use of RLX to manage dermal fibrosis should focus their attention on RLX receptor system.
Bennet RG. Relaxin and its role in the development and treatment of fibrosis. Transl Res 2009;145:1-6.
Khanna D, Clements PJ, Furst DE, Korn JH, Ellman M, Rothfield N, Wigley FM, Moreland LW, Silver R, Kim YH, Steen VD, Firestein GS, Kavanaugh AF,Weisman M, Mayes MD, Collier D, Csuka ME, Simms R, Merkel PA, Medsger TA Jr, Sanders ME, Maranian P, Seibold JR; Relaxin Investigators and the Scleroderma Clinical Trials Consortium. Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvment: a randomized, double-blind, palcebo-controlled trial. Arthritis Rheum 2009;60:1102-1111.
Disclosure of Interest None declared