Study of the incidence of osteoporosis in patients with Sjögren's syndrome (pSS) and investigation of activation of the RANKL /RANK and osteoprotegerin (OPG) system.

Abstract

Primary Sjogren’s syndrome (pSS) is a common chronic autoimmune disease affecting 0.5–4.8% of the population. It is characterized by lymphocytic infiltration of exocrine glands - mainly salivary and lacrimal - resulting in oral and ocular dryness, although any organ system can virtually be affected. Among all autoimmune diseases, pSS has the highest risk for development of non-Hodgkin’s lymphoma (NHL) and approximately 10% of patients with SS associated with increased risk for B-cell lymphoma development and high mortality rates. In pSS there are various systemic manifestations; such as arthritis, rashes, Raynaud’s phenomenon, peripheral neuropathy and glomerulonephritis.1,2 While over the past few years, the importance of coexistence in the context of systemic autoimmune diseases such as subclinical atherosclerosis and osteoporosis has been extensively studied in pSS, data on the incidence and underlying pathophysiological mechanisms of osteopenia/osteoporosis are limited. In particular, osteopenia and osteoporosis levels appear to be elevated in patients with systemic autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis.3–5 Patients with pSS display a set of clinical and serological features that could possibly lead to reduced bone remodelling and reduced bone mineral density (BMD); such as low vitamin D levels, hypercalciuria associated with underlying interstitial nephritis, steroid use, as well as coexistence with other autoimmune disorders associated with an increased risk of osteoporosis such as primary biliary cirrhosis, celiac disease and distal renal tubular acidosis (dRTA). A strong relationship between the Wingless-type signalling pathway (Wnt) and pathophysiology of osteoporosis has been recognized, as mutations in that pathway lead to reduced bone density.(6) 77 with rheumatoid arthritis (RA A recent study found reduced bone density in pSS patients compared to reduced levels of DKK1 (Dickkopf-related protein 1) in the Wnt pathway, where it may be due to inhibition of bone formation.7 Another equally important signalling pathway crucial for bone homeostasis is the molecular pathway of RANKL and osteoprotegerin (OPG).7,8 Nf-κB receptor activating factor (RANK), its ligand (RANKL) and osteoprotegerin (OPG) - all members of the cytokine tumour necrosis factor (TNF) superfamily - play an important role in bone homeostasis as principal osteoclastogenic factors.8 RANKL is expressed by syno-vial cells, bone marrow stromal cells and osteocytes, and is secreted by osteoblasts and immune cells; such as activated T cells, including Tregs and activated B cells and lymphoid tissue cells.(9–13) The expression of RANKL is modulated by various cytokines upon stimulation by memory B cells, including interleukin-1 (IL-1), IL-6, IL-11, IL-12, IL-15 and TNF-α, glucocorticoids and parathyroid hormone.12–16 Osteoprotegerin acts as a competitive antagonist receptor, which binds membrane protein RANK and soluble RANKL molecule, plays an osteoprotective role.17 RANKL prevents bone reconstruction while OPG inhibits this action, effectively promoting bone reconstruction. The RANKL / OPG ratio appears to be the key to maintaining bone homeostasis. The RANKL / RANK / OPG signalling pathway has been shown to be activated in many autoimmune disorders, such as RA and systemic lupus erythematosus (SLE), with a role in the development of bone erosions and osteoporosis.14,18,19