Abstract
Rheumatoid arthritis (RA) is closely associated with periarticular osteopenia and leads to a high risk of generalized osteoporosis. Although glucocorticoid (GC) treatment ameliorates joint degradation and manages inflammation in RA, GC application may induce further bone quality deterioration in RA patients. Current treatments for RA lack relevant strategies for the prevention and treatment of osteopenia in RA. In this study, we aimed to investigate whether salvianolate treatment ameliorated osteopenia in prednisone-treated RA rats. Lewis rats with collagen-induced arthritis (CIA) were administered prednisone (PDN) or PDN plus salvianolate (PDN+Sal) treatment for 90 days. The effects of Sal were investigated in PDN-treated CIA rats. To further evaluate the effects of Sal under inflammatory conditions, we investigated the effects of Sal treatment on the TNF-α-induced inflammatory response in MC3T3-E1 osteoblasts. Bone histomorphometry, bone mineral density (BMD), bone biomechanical properties, micro-computed tomography (micro-CT), immunohistochemistry, RT-PCR and western blot analyses were performed to evaluate the effects of Sal. The results demonstrated that RA induced bone loss and bone quality deterioration, with high bone turnover in CIA rats. PDN+Sal treatment significantly increased BMD and trabecular/cortical bone mass, suppressed inflammation, and improved bone biomechanical properties compared to CIA control and PDN treatment. PDN+Sal treatment significantly suppressed bone resorption and the RANKL and RANKL/OPG ratios compared to PDN. PDN+Sal and PDN treatment significantly inhibited TNF-α by 82 and 83%, respectively, and both suppressed inflammation in CIA rats. However, there was no significant difference between PDN+Sal and PDN treatment alone in regard to bone formation parameters or the management of inflammation and arthropathy. Sal significantly increased Osterix, OPN, and Col1a1 while decreasing RANKL, TRAF6, and TRAIL gene in TNF-α-induced MC3T3-E1 osteoblasts. Sal significantly increased Osterix, OPN and RUNX2 while decreasing NF-κB, TRAF6 and IL-1β protein in TNF-α-induced MC3T3-E1 osteoblasts. The results suggested that salvianolate treatment ameliorated osteopenia and improved bone quality in prednisone-treated RA rats, and the potential mechanism may be related to the regulation of the RANKL/RANK/OPG signaling pathway, TRAIL-TRAF6-NFκB signal axis, and downregulation of inflammatory cytokines. Salvianolate could be used as a promising supplemental therapeutic strategy to ameliorate osteopenia and improve bone quality in GC-treated RA patients.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease that often leads to severe joint damage, disability and even death (Guler-Yuksel et al, 2010)
There is a large amount of evidence suggesting that accelerated Bone mineral density (BMD) loss occurred in the hands, spine and femoral neck of RA patients compared to that in healthy individuals (Guler-Yuksel et al, 2010; Fassio et al, 2016)
Our data showed that CIA induced significant joint destruction and inflammation, and systemic osteoporosis was found in CIA rats with trabecular and cortical bone degradation, BMD reduction, and bone biomechanical deterioration (Figures 1–3)
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease that often leads to severe joint damage, disability and even death (Guler-Yuksel et al, 2010). Current treatments for RA, such as nonsteroidal antiinflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), biologics and glucocorticoids (GCs), have limited bone protection effects and even accelerate bone loss around joints or induce generalized osteopenia. GCs play an important role in the treatment of severe RA patients Their potent anti-inflammatory effect significantly ameliorates RA symptoms; their potential side effects (e.g., GCinduced osteoporosis, GIOP) significantly limits the application of GCs in RA. Another report indicated that GCs (dosage ≥ 7.5 mg/day) were related to treatment failure in osteoporotic patients with RA (Wen et al, 2016)
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