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. 2025 May 9;20(1):450.
doi: 10.1186/s13018-025-05722-2.

Parthenolide ameliorates glucocorticoid-induced inhibition of osteogenic differentiation and osteoporosis by activating ERK signaling pathway

Yanling Feng  1 , Zhaoyang Li  2
Affiliations

Parthenolide ameliorates glucocorticoid-induced inhibition of osteogenic differentiation and osteoporosis by activating ERK signaling pathway

Yanling Feng et al. J Orthop Surg Res. .

Abstract

Background: Parthenolide (PTL) is a natural sesquiterpene lactone that possesses significant effects on stimulating osteoblast differentiation. The present study focused on the potential of PTL in the treatment of glucocorticoid-induced osteoporosis (GIOP).

Methods: MC3T3-E1 cells were treated with dexamethasone (DEX; 10 µM) or/and PTL (5, 10, and 20 µM). The changes in osteogenic differentiation were analyzed by conducting ALP and Alizarin Red staining and assessing the levels of osteogenic markers (Runx2, Osx, and OPN). PTL (3 and 10 mg/kg/day) was injected into rat models of GIOP induced by DEX. Bone formation was analyzed by assessing the levels of bone turnover markers (ALP, TRAP, OCN, and CTx) in the serum and osteoblast differentiation markers (BMP2 and Runx2) in the femurs. The pathological changes of the femurs were determined by H&E staining. Bone mass and osteoblast numbers in the femurs were measured. Western blotting evaluated ERK phosphorylation in vitro and in vivo.

Results: PTL promoted osteogenic differentiation and enhanced the levels of Runx2, Osx, OPN, and ERK phosphorylation in DEX-treated MC3T3-E1 cells. ERK inhibitor U0126 reversed the promoting effect of PTL on osteogenesis in DEX-treated MC3T3-E1 cells. After the administration of PTL in rat models of GIOP, the levels of ALP, TRAP, OCN, and CTx in the serum and the levels of BMP2, Runx2, and ERK phosphorylation in the femurs were restored. PTL increased trabecular bone number, reduced trabecular separation, and increased the number of osteoblasts in GIOP rat model.

Conclusion: Overall, PTL alleviates osteoporosis by promoting osteogenic differentiation via activation of ERK signaling.

Keywords: Bone formation; ERK; Glucocorticoid; Osteoporosis; Parthenolide.

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Conflict of interest statement

Declarations. Ethics approval: All animal procedures were carried out in accordance with the principles of the Ethics Committee of The Second Hospital of Lanzhou University (No. D2025-356). Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
PTL regulates bone formation and bone resorption in GIOP rat model. (A) Serum levels of ALP, (B) TRAP, (C) OCN, (D) and CTx in GIOP rats were evaluated by corresponding detection kits. (E-F) Western blotting of BMP2 and Runx2 protein levels in the femurs. (G-H) Western blotting of ERK phosphorylation in the femurs. N = 10. **p < 0.01 vs. control group; #p < 0.05, ##p < 0.01 vs. DEX group. PTL, parthenolide; DEX, dexamethasone; ALP, alkaline phosphatase; TRAP, tartrate-resistant acid phosphatase; OCN, osteocalcin; CTx, C-terminal telopeptide of type I collagen; GIOP, glucocorticoid-induced osteoporosis; BMP2, bone morphogenetic protein 2; Runx2, runt-related transcription factor 2; ERK, extracellular signal-regulated kinase
Fig. 2
Fig. 2
PTL promotes osteogenesis and activates ERK signaling in DEX-treated MC3T3-E1 cells. RT-qPCR analysis of (A) Runx2, (B) Osx, and (C) OPN mRNA expression, and (D-E) western blotting of the levels of Runx2, Osx, and OPN proteins and (F-G) ERK phosphorylation in MC3T3-E1 cells treated with DEX and PTL for 7 days. N = 3. *p < 0.05, **p < 0.01 vs. OM group; #p < 0.05, ##p < 0.01 vs. DEX group. PTL, parthenolide; DEX, dexamethasone; OM, osteogenic medium; Runx2, runt-related transcription factor 2; Osx, osterix; OPN, osteopontin; ERK, extracellular signal-regulated kinase
Fig. 3
Fig. 3
PTL accelerates osteogenic differentiation of MC3T3-E1 cells by activating ERK signaling. (A-B) Western blotting assessed the levels of ERK phosphorylation in MC3T3-E1 cells treated with DEX, PTL, and U0126. (C-D) ALP staining and (E-F) Alizarin Red staining in MC3T3-E1 cells treated with DEX, PTL, and U0126. N = 3. **p < 0.01 vs. OM group; #p < 0.05, ##p < 0.01 vs. DEX group; &&p < 0.01 vs. PTL group. PTL, parthenolide; DEX, dexamethasone; ALP, alkaline phosphatase; OM, osteogenic medium; ERK, extracellular signal-regulated kinase
Fig. 4
Fig. 4
PTL accelerates osteogenic differentiation of MC3T3-E1 cells. (A) CCK-8 assay evaluated the viability of MC3T3-E1 cells after treatment with PTL. (B) CCK-8 assay showed the viability of MC3T3-E1 cells after treatment with DEX and PTL. (C-D) ALP staining (7 days) and (E-F) Alizarin Red staining (14 days) in MC3T3-E1 cells treated with DEX and PTL. N = 3. *p < 0.05, **p < 0.01 vs. control or OM group; ##p < 0.01 vs. DEX group. PTL, parthenolide; DEX, dexamethasone; ALP, alkaline phosphatase; OM, osteogenic medium
Fig. 5
Fig. 5
PTL increases bone mass and the number of osteoblasts in GIOP rat model. (A) H&E staining of the proximal femurs. Calculation of bone morphometric parameters including (B) Tb.Ar, (C) Tb.N, (D) Tb.Sp, and (E) N.ob/BS in the femurs. N = 10. **p < 0.01 vs. control group; #p < 0.05, ##p < 0.01 vs. DEX group. PTL, parthenolide; DEX, dexamethasone; GIOP, glucocorticoid-induced osteoporosis; Tb.Ar, trabecular area ratio; Tb.N, trabecular bone number; Tb.Sp, trabecular separation; N.ob/BS, osteoblast number/bone surface
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