Dual Role of Tanshinone IIA on the Differentiation and Function of Bone Cells: Regulation of Ca2+-oscillation in Osteoclasts

Tanshinone IIA (TIIA), known as a major constituent of Salvia miltiorrhiza Bunge, exhibits anti-inflammatory and anti-osteoporotic activities. In this study, we investigated the effects of TIIA and its regulatory mechanism on osteoclast and osteoblast differentiation. TIIA significantly inhibited the formation of TRAP(+)-mature osteoclasts and resorption pits in a dose-dependent manner. The expression of the osteoclast differentiation marker genes and activation of JNK, p38, and IκB were remarkably suppressed by TIIA during osteoclastogenesis. In addition, TIIA removed RANKL-induced Ca²⁺ oscillations through sequential inactivation of Bruton's tyrosine kinase (BTK) and phospholipase C gamma (PLCγ1 and 2). Consequently, the expression of pivotal transcription factors in osteoclastogenesis, c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (Nfatc1), was remarkably decreased. By contrast, TIIA stimulated the expression of osteoblast differentiation markers and transcription factors including Runx2, resulting in increased nodule formation. Interestingly, TIIA dose-dependently suppressed osteoclast formation in coculture with bone marrow cells (BMs) and osteoblasts via inhibiting the expression of Rankl and Csf-1 (M-csf) on osteoblasts. These findings indicate that TIIA serves as a dual modulator of bone remodeling, suppressing osteoclast-mediated resorption while enhancing osteoblast-mediated formation, thereby supporting its potential as a therapeutic candidate for resorptive bone diseases.