Oral dosing of pentoxifylline, a pan-phosphodiesterase inhibitor restores bone mass and quality in osteopenic rabbits by an osteogenic mechanism: A comparative study with human parathyroid hormone

Pal, Subhashis; Porwal, Konica; Khanna, K. N.; Gautam, Manoj; Malik, Monika; Rashid, Mamunur; Macleod, John; Wahajuddin, Muhammad; Parameswaran, Venkitanarayanan; Bellare, Jayesh; Chattopadhyay, Naibedya

doi:10.1016/j.bone.2019.03.010

Cited by 14 publications

(11 citation statements)

References 44 publications

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“…After completion of time, the cells were fixed with 4% para formaldehyde (PFA) for 30 min at room temperature and stained with 40 mM alizarin red S, which stains nascent calcium and quantified with 10% Cetylpyridinium chloride (CPC) solution. The absorbance was taken at 595 nm on the next day ( 21 ).…”

Section: Methodsmentioning

confidence: 99%

MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway

Tripathi

John²,

Kumar³

et al. 2022

Front. Endocrinol.

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X-linked hypophosphatemia (XLH), an inheritable form of rickets is caused due to mutation in Phex gene. Several factors are linked to the disease’s aetiology, including non-coding RNA molecules (miRNAs), which are key post-transcriptional regulators of gene expression and play a significant role in osteoblast functions. MicroRNAs sequence analysis showed differentially regulated miRNAs in phex silenced osteoblast cells. In this article, we report miR-539-3p, an unidentified novel miRNA, in the functional regulation of osteoblast. MiR-539-3p overexpression impaired osteoblast differentiation. Target prediction algorithm and experimental confirmation by luciferase 3’ UTR reporter assay identified LRP-6 as a direct target of miR-539-3p. Over expression of miR-539-3p in osteoblasts down regulated Wnt/beta catenin signaling components and deteriorated trabecular microarchitecture leading to decreased bone formation in ovariectomized (Ovx) mice. Additionally, biochemical bone resorption markers like CTx and Trap-5b were elevated in serum samples of mimic treated group, while, reverse effect was observed in anti-miR treated animals along with increased bone formation marker P1NP. Moreover, transcriptome analysis with miR-539-3p identified a novel uncharacterized Akap-3 gene in osteoblast cells, knock down of which resulted in downregulation of osteoblast differentiation markers at both transcriptional and translational level. Overall, our study for the first time reported the role of miR-539-3p in osteoblast functions and its downstream Akap-3 signalling in regulation of osteoblastogenesis.

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Section: Methodsmentioning

confidence: 99%

MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway

Tripathi

John²,

Kumar³

et al. 2022

Front. Endocrinol.

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“…Pentoxifylline [3,7-dimethyl-1-(5-oxohexyl) purine-2,6-dione], a synthetic xanthine derivative, has also been reported to have a positive effect on bone homeostasis. Oral administration or subcutaneous injection of pentoxifylline for several weeks, increased the bone mass and bone strength under normal and pathological conditions [20][21][22]. These previous reports suggest that some of the synthetic xanthine derivatives have positive effects on bone regeneration.…”

Section: Introductionmentioning

confidence: 63%

Stimulatory Effects of KPR-A148 on Osteoblast Differentiation and Bone Regeneration

Lim

Kim

Lee

et al. 2019

Tissue Eng Regen Med

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BACKGROUND: Xanthine derivatives have been used to treat a variety of medical conditions including respiratory disease and neural degeneration. However, few studies have reported their effects on bone regeneration. Therefore, we investigated the effects of KPR-A148, a synthetic xanthine derivative on osteoblast differentiation in vitro and bone regeneration in vivo. METHODS: The cytotoxicity of KPR-A148 was evaluated using MC3T3-E1 cells by the 3-(4,5-dimethylthiazolyl-2)-2,5diphenyltertrazolium bromide assay. The effects of KPR-A148 on osteoblast differentiation were examined by alkaline phosphatase staining, Alizarin red S staining, and real-time PCR of osteoblast differentiation marker genes. To investigate the effects of KPR-A148 on in vivo bone regeneration, a KPR-A148-containing collagen sponge was implanted into a mouse calvarial defect and KPR-A148 was injected twice, weekly. Bone regeneration was evaluated quantitatively by micro-CT and qualitatively by hematoxylin and eosin, as well as Masson's Trichrome staining. RESULTS: KPR-A148 did not show toxicity in the MC3T3-E1 cells and promoted osteoblast differentiation in a concentration-dependent manner. 10 lM of KPR-A148 showed the most significant effect on alkaline phospatase staining and matrix mineralization. KPR-A148 increased the expression of osteoblast marker genes in both the early and late stages of differentiation. In addition, KPR-A148 significantly induced new bone formation in the calvarial defect model. CONCLUSION: These results demonstrate that KPR-A148 strongly induces osteoblast differentiation and new bone formation. Therefore, it could be used as a potential therapeutic agent for regenerating bone following its destruction by disease or trauma.

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“…At the beginning, we performed ALP and ARS staining [ 27 , 28 ] to determine that INF 39 accelerated osteogenesis in both the early and late stages in a dose-dependent manner. The osteoblast-related genes, including ALP , COL1a , Runx2 , and OCN [ 29 , 30 ], had a higher expression in the INF 39-treated groups than in the control group. Accordingly, the expression of specific proteins, such as ALP and Runx2, was elevated in the INF 39-treated groups than in the control group.…”

Section: Discussionmentioning

confidence: 99%

A Novel Inhibitor INF 39 Promotes Osteogenesis via Blocking the NLRP3/IL‐1β Axis

Chen

Tang

Fan

et al. 2022

BioMed Research International

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Purpose. A balance between osteoblasts and osteoclasts is essential to maintain skeletal integrity, regulating bone metabolism and bone remodeling. The nucleotide binding oligomerization domain, leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome is known as a cytosolic complex involved in producing proinflammatory cytokines consisting of interleukin- (IL-) 1β, which accelerates the occurrence of osteoporosis. Therefore, we aimed to investigate the effect of a novel NLRP3 inhibitor INF 39 on bone formation and bone resorption. Material and Methods. Cell viability of INF 39-treated osteoclasts and calvarial osteoblasts was tested by CCK-8 assays. Quantitative RT-PCR (qRT-PCR) was used to evaluate gene expression level during osteoblast and osteoclast formation. Western blot analysis was used to determine the effect of INF 39 on osteogenic and osteoclast-related proteins. Result. It was shown that INF 39 promotes osteoblast differentiation via inhibiting NLRP3, thereby reducing the production of IL-1β dependent on NLRP3 in vitro. However, RANKL-induced osteoclast differentiation is not influenced by INF 39 in vitro. Conclusion. Our study suggests that NLRP3 could be a new target and INF 39 may be a potential option for prevention and treatment of osteoporosis.

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Oral dosing of pentoxifylline, a pan-phosphodiesterase inhibitor restores bone mass and quality in osteopenic rabbits by an osteogenic mechanism: A comparative study with human parathyroid hormone

Cited by 14 publications

References 44 publications

MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway

MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway

Stimulatory Effects of KPR-A148 on Osteoblast Differentiation and Bone Regeneration

A Novel Inhibitor INF 39 Promotes Osteogenesis via Blocking the NLRP3/IL‐1β Axis

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