Gottron's Papules Exhibit Dermal Accumulation of CD44 Variant 7 (CD44v7) and Its Binding Partner Osteopontin: A Unique Molecular Signature

Abstract

The accumulated mucin in non-Gottron’s dermatomyositis (DM) lesions is primarily chondroitin-4-sulfate (C4S), which is immunomodulatory in vitro. Gottron’s papules are a particularly resistant manifestation of DM that often persist after other lesions have resolved with therapy. We examined non-Gottron’s DM lesions and Gottron’s papule skin biopsies for C4S, CD44v7, a CS-binding isoform causally implicated in autoimmunity, and osteopontin, a CD44v7 ligand implicated in chronic inflammation. Gottron’s papule dermis contained more C4S and CD44v7 than non-Gottron’s lesions. Normal skin showed less CD44v7 over joints relative to Gottron’s lesions. All DM dermis had increased osteopontin compared to healthy skin. Mechanically stretching cultured fibroblasts for six hours induced CD44v7 mRNA and protein, while IFN-γ treatment induced OPN mRNA and protein. Osteopontin alone did not induce CD44v7, but stretching dermal fibroblasts in the presence of osteopontin increased THP-1 monocyte binding, which is blunted by anti-CD44v7 blocking antibody. C4S, CD44v7, and osteopontin are three molecules uniquely present in Gottron’s papules that contribute to inflammation individually and in association with one another. We propose that stretch-induced CD44v7 over joints, in concert with dysregulated osteopontin levels in the skin of DM patients, increases local inflammatory cell recruitment and contributes to the pathogenesis and resistance of Gottron’s papules.

Measurement of cytokines and chemokines and association with clinical severity of dermatomyositis and clinically amyopathic dermatomyositis

“…The mechanism of cutaneous manifestations in DM has not yet been elucidated. Cellular immunity, cytokine pathways, mechanical stress and sun exposure are possible contributors in the pathogenesis . In accordance with previous studies, we found serum levels of IL‐10, IL‐18 and CXCL10 to be significantly elevated in patients with DM and CADM compared with healthy controls.…”

Differential RNA Expression Profile of Skeletal Muscle Induced by Experimental Autoimmune Myasthenia Gravis in Rats

“…OPN is a glycosylated phosphoprotein originally identified in bone matrix, but now found to be produced in many cell types. OPN is considered a pro-inflammatory cytokine, and increased levels have been associated with inflammatory muscle disease (Urganus et al, 2009; Niewold et al, 2010; Kim et al, 2012) and muscular dystrophy (Kyriakides et al, 2011). Its elevated expression is in distinction from the upregulation of an anti-inflammatory state of RNA profile, which would support the contention that EOM has a unique immune environment, which in certain conditions enhances susceptibility to autoimmune and inflammatory disorders (Soltys et al, 2008).…”

Cannabinoid Reduces Inflammatory Cytokines, Tumor Necrosis Factor-α, and Type I Interferons in Dermatomyositis In Vitro

“…The key inflammatory cytokines in dermatomyositis are type-I interferons (IFN) and tumor necrosis factor alpha (TNFα) (Kim et al, 2012, Nabatian et al, 2012, Pachman et al, 2000). We hypothesized that ajulemic acid could suppress production of these cytokines from immune cells of dermatomyositis patients in vitro .…”