Protective effects and possible mechanisms of Salvia miltiorrhiza-derived interventions in animal models of osteoarthritis: a preclinical systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge, commonly known as Danshen, is a traditional Chinese medicinal herb historically used for blood stasis- and pain-related disorders. Its extracts and bioactive constituents have shown anti-inflammatory, antioxidant, anti-apoptotic, and tissue-protective effects, suggesting potential value for osteoarthritis (OA).

AIM OF THE STUDY: This systematic review and meta-analysis evaluated the protective effects and possible mechanisms of Salvia miltiorrhiza-derived interventions in animal models of OA.

MATERIALS AND METHODS: PubMed, EMBASE, Web of Science, Scopus, CNKI, and Wanfang were searched from inception to March 2026. Controlled in vivo animal studies assessing Salvia miltiorrhiza-derived interventions or related constituents in OA models were included. Primary outcomes were histological cartilage damage scores, including OARSI and Mankin scores. Secondary outcomes included inflammatory cytokines, cartilage matrix metabolism markers, apoptosis-related indicators, and oxidative stress markers. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated.

RESULTS: Twenty-two studies involving 456 animals were included. Salvia miltiorrhiza-derived interventions significantly attenuated histological cartilage damage, as reflected by lower OARSI scores (SMD = -4.20, 95% CI -5.31 to -3.09; I2 = 69.26%) and Mankin scores (SMD = -6.50, 95% CI -8.50 to -4.50; I2 = 85.61%). Model type showed a significant subgroup difference for OARSI score, and intervention category showed a significant subgroup difference for Mankin score, suggesting possible sources of heterogeneity. Significant reductions were observed in serum IL-1β, serum IL-6, cartilage/chondrocyte IL-6, and serum TNF-α, whereas the reduction in cartilage TNF-α did not reach statistical significance. Salvia miltiorrhiza-derived interventions also increased Aggrecan and Collagen II expression and modulated MMP-13 expression, supporting an improvement in cartilage matrix homeostasis. Apoptosis-related analyses showed increased Bcl-2 expression and reduced caspase-3 expression and TUNEL-positive apoptotic cells, whereas the reduction in Bax expression was not statistically significant. Cartilage MDA levels were also significantly reduced. Leave-one-out sensitivity analysis indicated that the pooled OARSI result was robust. Although funnel plot asymmetry was observed, trim-and-fill analysis did not alter the direction of the pooled effect.

CONCLUSIONS: Current preclinical evidence suggests that Salvia miltiorrhiza-derived interventions may attenuate cartilage structural damage in animal models of OA, with possible involvement of inflammatory responses, extracellular matrix metabolism, chondrocyte apoptosis, and oxidative stress. However, these findings should be interpreted cautiously because of substantial heterogeneity across several outcomes, small sample sizes, limited numbers of studies for several mechanistic endpoints, wide uncertainty in some model-based sensitivity analyses, and incomplete reporting of key methodological safeguards. Overall, these results support further investigation of Salvia miltiorrhiza-derived interventions in OA-related preclinical research, but more rigorously designed, standardized, and independently replicated animal studies are needed before clinical translation can be considered.