TABLE 3.

Effects and mechanisms of SM and its constituents on osteoclasts and osteoblasts.

Compounds	Osteoclast/Osteoblast and intervention	Results	References
Osteoclasts differentiation and osteoclastic bone resorption
Cryptotanshinone (CPT)	Cell: RAW 264.7 Model: RANKL-induced osteoclast differentiation Treatment: 1 and 10 µM of CPT for 1 h	↓Osteoclast differentiation, TRAP activity ↓NFATc1, c-fos, cathepsin K	Yang et al. (2022)
Tanshinone IIA	Cell: RAW264.7 Model: RANKL and M-CSF-induced osteoclast differentiation Treatment: Tanshinone IIA (1, 2, 5 μg/mL) for 7 days	↓TRAP+ cells, resorption pits, NFATc1, TRAP, MMP-9, cathepsin K, CTR, TRAF6, p-p65/p65, p-p50/p50, p-IκBα/IκBα, p-ERK/ERK, p-JNK/JNK, and p-P38/P38, p-Akt/Akt, p-c-fos/c-fos	Cheng et al. (2018)
CPT	Cell: BMMS Model: RANKL-induced osteoclast differentiation Treatment: 0.1–40 µM of CPT	↓Osteoclast differentiation, TRAP activity, TRAP+ osteoclasts, resorption area ↓TRAF6, NFATc1, c-fos, p-ERK/ERK, p-P65/P65	Wang et al. (2019c)
Tanshinones	Model: Cathepsin K mediated degradation of soluble collagen Treatment: Tanshinones (10 µM)	↓Degradation of soluble collagen	Panwar et al. (2018)
Dihydrotanshinone I (DTI)	Model: Cathepsin K mediated degradation of soluble and insoluble collagen Treatment: DTI (0.5–50 µM)	↓Degradation soluble collagen and gelatin ↓Degradation of insoluble collagen fiber ↓TRAP+ osteoclasts and resorption pits on bone surfaces	Panwar et al. (2016)
Dihydrotanshinone I (DTI)	Cell: RAW264.7 cells Model: RANKL-induced osteoclastogenesis Treatment: 1, 2 µM of DTI	↓Osteoclasts area, osteoclasts numbers ↓2 μM of DTI significantly inhibited the expressions of osteoclast-specific markers (Acp5, c-fos, NFATc1, CTSK, Atp6vod2), and phosphorylation of ERK and JNK, nuclear heterotopia of p65, degradation of IκBα protein	Ma et al. (2023)
Tanshinone IIA Sulfonic Sodium (T06)	Model: Cathepsin K-mediated degradation of soluble and insoluble collagen Treatment: T06 (0.5–50 µM)	↓Collagen degradation	Panwar et al. (2017)
Osteoblasts differentiation and osteoblast-mediated osteogenesis
SM aqueous extract (SMA)	Cell: Pre-osteoblast MG63 cells Model: H2O2 -treated cells Treatment: SMA (5, 10, 15 μg/mL) for 24 h	↑Cell viability ↑ALP activity ↓Intracellular ROS levels	Dong et al. (2018)
Tanshinol	Cell: MG cells and EA cells Model: Dex-treated cells Treatment: Tanshinol (dose was not mentioned) for 24 h	↑Migration and tube formation of EA cells ↑VEGFR2 and β-catenin proteins in MG cells and EA cells Supernatants from EA cells promoted the expressions of VEGFR2 and β-catenin in MG cells	Lai et al. (2021)
Tanshinol	Cell: Pluripotent mesenchymal precursor C2C12 cells and pre-osteoblastic MC3T3-E1 cells Model: Dex (1 µM) and/or RU486 (GC receptor antagonist) and/or siRNA-KLF15 -treated cells Treatment: Tan (1 µM)	↑Osteoblastic differentiation (ALP staining) ↑Bone formation (Alizarin Red S) ↓KLF15 mRNA	Yang et al. (2016)
Tanshinol	Cell: MC3T3-E1 Model: Normal cultured MC3T3-E1 Treatment: 0–400 μg/mL of tanshinol for 4 days or 48 h	↑Osteoblast viability and ALP activity ↓Apoptosis (↑Bcl-2/Bax; ↓apoptotic area) ↑mRNA and protein expressions of Col1A1, Runx2 and OCN	Han and Wang (2017)
Sal B and Tanshinol	Cell: BMSCs Model: Osteogenic induction of MSCs (OB-IN) Treatment: 0.05, 0.5, 2.5 µM of Sal B and 2 µM of Danshensu	↑ALP activity and OCN ↑OPG, OPG/RANKL ↑NO secretion ↓RANKL	Zhang et al. (2017)
Sal B	Cell: Primary osteoblasts were isolated from the skull of 3-day-old SD rat Model: SMG-induced osteoblasts	↑Osteoblast proliferation, ALP activity ↓Apoptosis ↓Oxidative stress (↑SOD, CAT, LDH, GSH-Px; ↓MDA) ↑Osteogenesis: Runx2, Osx, OPN, ALP, Col-I ↑Antioxidant: Nrf2, HO-1	Wang et al. (2018)
Sal B	Cell: Primary osteoblasts were isolated from the skull of SD rats Model: 10–6 μg/mL prednisolone acetate (PA) stimulated osteoblast Treatment: Sal B (dose was not provided)	↑ALP activity ↑Antioxidant: Nrf2 ↑Osteoblasts differentiation: Runx2 and Osx ↑Osteogenesis: Col-I, IGF-I and OCN	Qiao et al. (2019)
Sal B	Cell: Human mesenchymal stem cells (hMSCs) Model: Osteogenic induced medium (OIM) induced hMSCs Treatment: Sal B (0.1, 0.5, 1 and 5 µM)	↑ALP activity, mineralization of hMSCs ↑Runx2, Osx, OPN, OCN, p-ERK/ERK	Xu et al. (2014)
Sal B	Cell: MC3T3-E1 and 3T3-L1 Model: TAZ knock-down cells Treatment: Sal B (0.1, 1 and 10 μmol/L) for 3, 7 or 14 days	↑Osteogenesis (TAZ, Runx2 and OCN) in MC3T3-E1 cells ↓Adipogenesis (↓C/EBPβ and PPARγ; ↑TAZ) in 3T3-L1 cells ↑p-ERK/ERK in both cell lines TAZ knock-down counteracts upregulation of Runx2 and OCN expressions and downregulation of C/EBPβ and PPARγ expressions in 3T3-L1 cells in response to Sal B treatment	Wang et al. (2019b)
Tanshinone IIA (Tan IIA)	Cell: Human periodontal ligament stem cells (hPDLSCs) Model: Normal cultured hPDLSCs Treatment: Tan IIA (2.5 and 5 µM)	↑Proliferation of hPDLSCs ↑Osteoblasts differentiation of hPDLSCs: Alizarin red-positive calcium deposition; mRNA and protein expressions of ALP, OPN, OCN, Runx2 ↓Adipogenic differentiation of hPDLSCs: mRNA expressions of LPL and PPARγ; Oil red O-positive cytoplasmic lipid accumulation ↓Apoptosis of hPDLSCs: C-PARP, Ccaspase-3	Liu et al. (2019)
Tan IIA	Cell: Osteoblastic MC3T3-E1 cells Model: Dex (1 µM)-induced cell apoptosis Treatment: Tan IIA (1 µM)	↑Cell viability Attenuated Dex-induced apoptosis ↓Cytosol cytochrome C, Bax, activity of caspase-9/-3 ↑Bcl-2 ↓ROS, Nox4	Li et al. (2015)
Tan IIA	Cell: BMSCs isolated from the mandible of OVX rats Model: OVX-induced BMSC senescence Treatment: Tan IIA (20 µM)	↑Proliferation of BMSCs ↑Protein levels of BMSCs: Nanog, SOX2 and octamer-binding transcription factor 4 (OCT4) ↓mRNA expression of PHGDH ↓BMSCs senescence: SA-β-gal positive cells	Wang et al. (2019a)
Tan IIA	Cell: Mouse BM-MSCs Model: Osteogenic differentiation of mouse BM-MSCs Treatment: Tan IIA (1, 5, 10, and 20 µM)	1, 5 µM of Tan IIA ↑ALP activity, calcium concentration ↑Gene expressions of OPN, Col-I, OPG, Runx2, BMP-4, β-catenin, and Cyclin D1 ↓Gene expressions of RANKL 10 µM of Tan IIA: No changes 20 µM of Tan IIA ↓ALP activity, calcium concentration ↓Gene expressions of OPN, Col-I, OPG, Runx2, BMP-4, β-catenin, and Cyclin D1 ↑Gene expression of RANKL	Qian et al. (2015)