Synthesis and biological activities of drugs for the treatment of osteoporosis

Zhou, Shiyang; Huang, Gangliang; Chen, Guang‐Ying

doi:10.1016/j.ejmech.2020.112313

Cited by 43 publications

(27 citation statements)

References 224 publications

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“…In the present study, we firstly found that the differentiation of MC3T3-E1 cells was dramatically promoted by treatment with Trelagliptin and verified by activated ALP and increased calcium nodules. Also, the expressions of the biomarkers of osteoblastic differentiation, ALP, OCN, OPN, and BMP-2 [ 34 , 35 ], were found to be greatly upregulated by treatment with Trelagliptin, indicating the inductive effect of Trelagliptin on osteoblastic differentiation. However, our data indicate that Trelagliptin alone did not have any influence on the expressions of osteoblast differentiation markers ALP, OCN, OPN, and BMP-2 when the cells were grown in basal growth media (Supplementary Figure 1), suggesting soluble osteogenic factors in osteogenic media are required for the modulation of Trelagliptin on osteogenic differentiation.…”

Section: Discussionmentioning

confidence: 99%

Trelagliptin stimulates osteoblastic differentiation by increasing runt-related transcription factor 2 (RUNX2): a therapeutic implication in osteoporosis

Shao

Cao

et al. 2021

Bioengineered

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Osteoporosis, an aging-associated bone metabolic disease, is affecting millions of people worldwide. The deregulated process of osteoblastic differentiation has been linked with the progression of osteoporosis. Trelagliptin is a long-acting inhibitor of DPP-4 used for the management of type 2 diabetes mellitus. However, it is unknown whether Trelagliptin possesses a beneficial effect in osteoblastic differentiation. Interestingly, we found that treatment with Trelagliptin enhanced differentiation and promoted the mineralization of MC3T3-E1 cells. Firstly, Trelagliptin increased the activity of alkaline phosphatase (ALP) and promoted osteoblastic calcium deposition. Additionally, treatment with Trelagliptin upregulated ALP, osteocalcin (OCN), osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2). Notably, Trelagliptin increased RUNX2, a major regulator of osteoblastic differentiation. Mechanistically, Trelagliptin upregulated the levels of p-AMPKα. Blockage of AMPK with compound C abolished the effects of Trelagliptin in RUNX2 and osteoblastic differentiation, suggesting the involvement of AMPK. Our findings suggest that Trelagliptin might possess a potential for the treatment of osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Trelagliptin stimulates osteoblastic differentiation by increasing runt-related transcription factor 2 (RUNX2): a therapeutic implication in osteoporosis

Shao

Cao

et al. 2021

Bioengineered

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“…The drugs currently used for osteoporosis are mainly of two types: drugs that promote bone formation, such as human parathyroid hormone 8 , 9 , and drugs that inhibit bone resorption, such as bisphosphonates (alendronate, zoledronate) and receptor activator of nuclear factor kappa-B ligand (rankl) neutralizing antibody (denosumab) 8 , 10 – 12 . Romosozumab is a new type of anti-osteoporosis drug that increases bone mass and reduces fracture risk 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

Beraprost ameliorates postmenopausal osteoporosis by regulating Nedd4-induced Runx2 ubiquitination

Zheng

Zhou

et al. 2021

Cell Death Dis

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Bone health requires adequate bone mass, which is maintained by a critical balance between bone resorption and formation. In our study, we identified beraprost as a pivotal regulator of bone formation and resorption. The administration of beraprost promoted differentiation of mouse bone mesenchymal stem cells (M-BMSCs) through the PI3K–AKT pathway. In co-culture, osteoblasts stimulated with beraprost inhibited osteoclastogenesis in a rankl-dependent manner. Bone mass of p53 knockout mice remained stable, regardless of the administration of beraprost, indicating that p53 plays a vital role in the bone mass regulation by beraprost. Mechanistic in vitro studies showed that p53 binds to the promoter region of neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) to promote its transcription. As a ubiquitinating enzyme, Nedd4 binds to runt-related transcription factor 2 (Runx2), which results in its ubiquitination and subsequent degradation. These data indicate that the p53–Nedd4–Runx2 axis is an effective regulator of bone formation and highlight the potential of beraprost as a therapeutic drug for postmenopausal osteoporosis.

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“…Local inflammation in the bone induces the production of pro-osteoclastogenic cytokines, including tumor necrosis factor-α (TNF-α) and interleukins (ILs), which promote the differentiation and activation of bone-resorbing osteoclasts by increasing the expression of receptor activator of nuclear factor κB ligand (RANKL) (Boyle et al, 2003;Boutet et al, 2017). Current pharmacological interventions, including estrogen replacements, bisphosphonates and anti-RANKL antibody (denosumab), exert somewhat beneficial effects against osteoclast-mediated osteolysis (McClung et al, 2006;Zhou et al, 2020). However, serious undesirable side effects, including cardiovascular events, nephrotoxicity, osteonecrosis of the jaw, atypical fractures and gastrointestinal distress, are becoming increasingly prominent, limiting their long-term use (Kotian et al, 2016;Patel et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The Novel Antioxidant Compound JSH-23 Prevents Osteolysis by Scavenging ROS During Both Osteoclastogenesis and Osteoblastogenesis

Mei

Zheng

et al. 2021

Front. Pharmacol.

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Inflammatory osteolysis is a pathological skeletal disease associated with not only the production of inflammatory cytokines but also local oxidative status. Excessive reactive oxygen species (ROS) promote bone resorption by osteoclasts and induce the apoptosis of osteoblasts. In consideration of the lack of effective preventive or treatments options against osteolysis, the exploitation of novel pharmacological compounds/agents is critically required. In our study, we found that a novel antioxidant compound, JSH-23, plays a role in restoring bone homeostasis by scavenging intracellular ROS during both osteoclastogenesis and osteoblastogenesis. Mechanically, JSH-23 suppressed RANKL-induced osteoclastogenesis, bone resorption and the expression of specific genes (including NFATc1, c-Fos, TRAP, CTSK and DC-STAMP) via inhibition of the NF-κB signaling pathway. Meanwhile, JSH-23 suppressed RANKL-induced ROS generation via the TRAF6/Rac1/NOX1 pathway and the enhanced expression of Nrf2/HO-1. In addition, JSH-23 attenuated H2O2-induced apoptosis and mineralization reduction in osteoblasts by reducing ROS production and enhancing Nrf2/HO-1 expression. Our in vivo results further revealed that JSH-23 exerts its protective effects on bone mass through its antioxidant activity. In conclusion, our results show that the application of JSH-23 might be a novel and plausible strategy for the treatment of osteolysis-related disease.

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Synthesis and biological activities of drugs for the treatment of osteoporosis

Cited by 43 publications

References 224 publications

Trelagliptin stimulates osteoblastic differentiation by increasing runt-related transcription factor 2 (RUNX2): a therapeutic implication in osteoporosis

Trelagliptin stimulates osteoblastic differentiation by increasing runt-related transcription factor 2 (RUNX2): a therapeutic implication in osteoporosis

Beraprost ameliorates postmenopausal osteoporosis by regulating Nedd4-induced Runx2 ubiquitination

The Novel Antioxidant Compound JSH-23 Prevents Osteolysis by Scavenging ROS During Both Osteoclastogenesis and Osteoblastogenesis

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