Betulinic acid synergically enhances BMP2-induced bone formation via stimulating Smad 1/5/8 and p38 pathways

Abstract

BackgroundHealing of bone defects is a dynamic and orchestrated process that relies on multiple growth factors and cell types. Bone morphogenetic protein 2 (BMP2) is a key growth factor for bone healing, which stimulates mesenchymal stem cells to differentiate into osteoblasts. Betulinic acid (BetA) is a natural pentacyclic triterpenoid from plants. This study aimed to examine combinatory effects of BetA and BMP2 on ectopic bone generation in mice.ResultsIn MC3T3-E1 preosteoblast culture, 10–15 μM of BetA increased the alkaline phosphatase (ALP) activity and expression levels of osteogenic marker genes without the decreased cell viability. In addition, BetA synergistically enhanced BMP2-induced gene expressions and mineralization with the enhancement of phosphorylation of Smad1/5/8 and p38. In an in vivo ectopic bone formation model, combination of BetA (50 μg) and BMP2 (3 μg) resulted in increases in the amount of new bone generation, compared with treatment with BMP2 alone. Histological studies showed that bone generation with cortical and trabecular structures was resulted from the combination of BetA and BMP2.ConclusionBetA can enhance in vivo osteogenic potentials of BMP2, possibly via stimulating Smad 1/5/8 and p38 pathways, and combination of both agents can be considered as a therapeutic strategy for bone diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0260-5) contains supplementary material, which is available to authorized users.

Silencing of Long Non-coding RNA SMAD5-AS1 Reverses Epithelial Mesenchymal Transition in Nasopharyngeal Carcinoma via microRNA-195-Dependent Inhibition of SMAD5

“…Moreover, our study further demonstrated the effects of SMAD5-AS1 and miR-195 on the BMP2/SMAD5 pathway. The translocation of pSMAD5 from the cytoplasm to the nucleus can be stimulated by BMP2 (20). Consistently, BMP2 overexpression was determined to stimulate the phosphorylation of SMAD5 in this study.…”

“…Bone morphogenetic protein 2 (BMP2), as a stimulator of the SMAD5 pathway (20), is reported to accelerate NPC cell migration and invasion as well as to induce EMT (21,22). We subsequently intended to explore whether the role of SMAD5-AS1/miR-195 in NPC was related to the BMP2/SMAD5 pathway.…”

Enhancement of tenogenic differentiation of rat tendon‐derived stem cells by biglycan

“…As a member of the SLRP family, BGN can coordinate with the transforming growth factor β (TGF-β) superfamily members to modify TGF-β/BMP activities and functions (Hildebrand et al, 1994 has been reported to be highly expressed in the developing flexor tendon and has positive effects on tendon repair (Macias et al, 1997;Mihelic et al, 2004). Consistent with that, in our study, we found that BMP7 strongly increased in the TDSCs that were It has been reported that BMP2 enhanced bone formation and osteoblast differentiation via stimulating Smad1/5/8 (Choi, Jeong, Kook, & Koh, 2016). It remains unclear why the activation of the same pathway results in different cellular responses.…”

Acute Thymic Involution and Mechanisms for Recovery

“…Several therapeutic agents such as betulinic acid have also been implicated in immune reconstitution and the reversal of ATI. These agents possess pharmacological properties that improve the cellular as well as humoral immunity (Choi et al 2016;Jine et al 2012;Mullauer et al 2010). Treatment with these agents enhances the total number of thymocytes, thus causing an increase in the thymus weight index (Yi et al 2010), and has a protective effect against DM-induced thymocyte apoptosis in mice (Yi et al 2016).…”