Background The critical question of what drives fibroblast activation in systemic sclerosis (SSc) remains unanswered. The Wnt pathway, a known regulator of osteoblastogenesis, has also emerged as a crucial mediator of the fibrotic process. It was recently reported that Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway, is absent from scleroderma skin1. No data exist on circulating levels and function of Dkk-1 in patients with SSc.
Objectives To assess: i) circulating levels and function of Dkk-1 in patients with SSc and ii) skin expression of Dkk-1 in SSc and investigate potential correlations with clinical and demographic characteristics.
Methods Circulating Dkk-1 levels were measured in 50 patients with SSc and 50 healthy subjects, age and sex matched, using an established solid phase immunoassay. The functional integrity of Dkk-1 was assessed by a functional ELISA which measures only Dkk-1 bound to LRP6 receptor. Skin biopsies were obtained from 12 patients with SSc and 5 healthy subjects and Dkk-1 skin expression was assessed by immunohistochemistry
Results Patients were predominantly female (84%) with a mean age (±SEM) of 57.3 (±2.1) years. Most had diffuse disease (64%) with a mean MRSS (±SEM) of 17.1 (±1.2) and a mean (±SEM) disease duration of 8 (±1.3) years. Circulating levels of Dkk-1 did not differ significantly in patients with SSc compared to healthy subjects (mean ±SEM: 1603±154 pg/ml vs 1889±95 pg/ml for patients with SSc and healthy subjects, respectively, p=0.1). We found no correlation of circulating Dkk-1 levels with age, gender, disease duration, disease type, MRSS, HAQ-DI, inflammatory markers and PFT's. Patients with SSc had similar functional Dkk-1 levels compared to healthy subjects (mean ± SEM: 257.8±89.5 pg/ml vs 325±74.9 pg/ml for patients with SSc and healthy subjects, respectively, p=ns). In all skin biopsies obtained from healthy subjects, Dkk-1 was expressed at the epidermis, appendices and spindle like cells in the dermis. In sharp contrast, no Dkk-1 expression could be detected in spindle-like cells in the dermis in all patients with SSc; only 2 patients exhibited a weak expression at the epidermis.
Conclusions Circulating levels and function of Dkk-1 are not impaired in patients with SSc despite the striking lack of skin expression. These data indicate that local factors suppress Dkk-1 expression in scleroderma skin
Akhmetshina et al. Nat Commun 2012.
Disclosure of Interest None declared