Salvianolate Ameliorates Osteopenia and Improves Bone Quality in Prednisone-Treated Rheumatoid Arthritis Rats by Regulating RANKL/RANK/OPG Signaling

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.

Tetrandrine inhibits RANKL-induced osteoclastogenesis by promoting the degradation of TRAIL

“…As per past reports, it can induce apoptosis in a variety of tumor cells, including osteosarcoma cells, without affecting most human cell types (Gamie et al 2017 ; Pan et al 2013 ). The research by Yen et al proved that TRAIL triggered osteoclast differentiation via a (necrosis factor receptor-associated factor-6) TRAF-6 dependent signal pathway, as also confirmed (Gao et al 2021 ; Yen et al 2012 ). Other experiments confirmed that microgravity induced the TRAIL expression in preosteoclast cells and promoted osteoclast differentiation (Sambandam et al 2016 ).…”

“…In addition, Tetrandrine inhibited TRAIL expression. Past articles have confirmed that decreased TRAIL can inhibit the differentiation of osteoclasts by inhibiting TRAF6 recruitment and ultimately inhibiting the activation of the NF-κB pathway (Gao et al 2021 ). Moreover, we confirmed that the upregulation and downregulation of TRAIL expression in BMMs promoted and inhibited osteoclastogenesis, respectively.…”

Osteopontin, a bridge links osteoarthritis and osteoporosis

“…Gao, et al. ( 58 ) demonstrated rheumatoid arthritis induced bone loss and bone quality deterioration, with high bone turnover in collagen-induced arthritis (CIA) rats. The CIA rats showed higher levels of IL-6, and TNF-α in serum accompanied by decreased mRNA and protein levels of Osx (Osterix), OPN which is induced by a TNF-α-induced inflammatory medium in vitro .…”

“…Gao et al. ( 58 ) found salvianolic treatment ameliorated osteopenia and improved bone quality in rats, the potential mechanism may rely on increasing Osx, OPN, and Col1a1 levels in TNF-α-induced MC3T3-E1 osteoblasts through regulating the RANKL/RANK/OPG signaling pathway. Monotropein was also found to play an important role in regulating the OPN metabolism in MC3T3-E1 cells.…”

Salvianolic acid C promotes osteogenic differentiation of bone marrow mesenchymal stem cells in osteoporotic rats through activation of AMPK/SIRT1 pathway

“…The results showed that SAC can promote osteogenic differentiation through the AMPK/SIRT1 pathway. At present, studies have shown that salvianolic acid esters improve osteopenia and bone mass in prednisone‐treated rheumatoid arthritis rats by regulating the RANKL/RANK/OPG signaling pathway, 24 but no study has investigated the effects of SAC on the AMPK/SIRT1 signaling pathway. There are also studies showing that salvianolic acid B can prevent bone loss, 25 but whether SAC also has this effect has not been clarified.…”