TABLE 4.

Studies on the effect of crocin on osteoblastic differentiation.

Reference	Models/Crocin doses	Main results	Conclusion
Baharara et al. (2014)	BMSCs/60–80 µM (600–800 mg/ml)	Increased alkaline phosphatase (ALP) activity, cell mineralization, and osteocalcin gene expression	crocin may have effect on osteoblastic differentiation of BMSCs
Kalalinia et al. (2018)	BMSCs/12.5–50 µM (125–500 mg/ml)	Increased ALZ intensity, ALP activity, and ALP mRNA expression, was not cytotoxic using MTT test and IC50 calculation	Crocin can be considered a safe substance to promote osteogenic differentiation of BMSCs
(B. Li et al., 2020 )	hBMSCs/10–50 µM (10–500 mg/ml)	Increased LAP activity, calcium nodules, and RUNX2, COL1A1, and OCN expression, decreased GSK- 3β phosphorylation	Crocin is effective in in-vitro and in-vivo osteogenic models
Zhu et al. (2019)	M2 macrophages and BMSCs/40 and 80 µM (400–800 mg/ml)	Promoted M2 phenotype that was decreased in anti-inflammatory cytokine-induced osteogenic differentiation of BMSCs in co-culture with pre-treated macrophages through inhibition of p38 and c-Jun N-terminal kinase signaling	Crocin has therapeutic potential for bone degenerative diseases through induction of M2 macrophage polarization, resulting in inflammation reduction and osteogenic differentiation of BMSCs
Koski et al. (2020)	hFOBs and MG-63 cell line, Rats/45 µg (450 mg/ml)	Increased osteoblast proliferation and decreased osteosarcoma viability and pro-apoptotic and anti-inflammatory effects in-vivo	Crocin has a potential therapeutic effect on osteosarcoma regulation and uses for wound healing during bone tissue regeneration