Sonic Hedgehog Regulates Bone Fracture Healing

Takebe, Hiroaki; Shalehin, Nazmus; Hosoya, Akihiro; Shimo, Tsuyoshi; Irie, Kazuharu

doi:10.3390/ijms21020677

Cited by 27 publications

(15 citation statements)

References 24 publications

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“…Osterix (Osx) is an essential transcription factor for osteoblast differentiation; bone cannot form without it. Takebe et al was able to observe Osx-positive cells on the surface of a newly formed bone matrix seven days after the fracture [46]. We saw very few Osx-positive cells, particularly in the + Sr and non-scaffold groups.…”

Section: Bone and Tissue Regenerationmentioning

confidence: 45%

Effects of Strontium-Doped β-Tricalcium Scaffold on Longitudinal Nuclear Factor-Kappa Beta and Vascular Endothelial Growth Factor Receptor-2 Promoter Activities during Healing in a Murine Critical-Size Bone Defect Model

Tohidnezhad

Kubo

Lichte

et al. 2020

IJMS

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It was hypothesized that strontium (Sr)-doped β-tricalcium phosphate (TCP)-based scaffolds have a positive effect on the regeneration of large bone defects (LBD). Readouts in our mice models were nuclear factor-kappa beta (NF-κB) activity and vascular endothelial growth factor receptor-2 (VEGFR-2) promoter activity during the healing process. A 2-mm critical-size femoral fracture was performed in transgenic NF-κB- and VEGFR-2-luciferase reporter mice. The fracture was filled with a 3D-printed β-TCP scaffold with or without Sr. A bioluminescence in-vivo imaging system was used to sequentially investigate NF-κB and VEGFR-2 expression for two months. After sacrifice, soft and osseous tissue formation in the fracture sites was histologically examined. NF-κB activity increased in the β-TCP + Sr group in the latter stage (day 40–60). VEGFR-2 activity increased in the + Sr group from days 0–15 but decreased and showed significantly less activity than the β-TCP and non-scaffold groups from days 40–60. The new bone formation and soft tissue formation in the + Sr group were significantly higher than in the β-TCP group, whereas the percentage of osseous tissue formation in the β-TCP group was significantly higher than in the β-TCP + Sr group. We analyzed longitudinal VEGFR-2 promoter activity and NF-κB activity profiles, as respective agents of angiogenesis and inflammation, during LBD healing. The extended inflammation phase and eventually more rapid resorption of scaffold caused by the addition of strontium accelerates temporary bridging of the fracture gaps. This finding has the potential to inform an improved treatment strategy for patients who suffer from osteoporosis.

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Section: Bone and Tissue Regenerationmentioning

confidence: 45%

Effects of Strontium-Doped β-Tricalcium Scaffold on Longitudinal Nuclear Factor-Kappa Beta and Vascular Endothelial Growth Factor Receptor-2 Promoter Activities during Healing in a Murine Critical-Size Bone Defect Model

Tohidnezhad

Kubo

Lichte

et al. 2020

IJMS

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“…Hedgehog signaling is involved in fracture healing. 167 In the early phase of fracture repair, the expression of SHH is detected in proliferating callus-forming cells in the periosteum. 168 SHH has an important role to facilitate both angiogenesis and osteogenesis in vivo and in vitro.…”

Section: Sonic Hedgehogmentioning

confidence: 99%

Bone Microvasculature: Stimulus for Tissue Function and Regeneration

Lee

Jain

Alimperti

2021

Tissue Engineering Part B: Reviews

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Bone is a highly vascularized organ, providing structural support to the body, and its development, regeneration, and remodeling depend on the microvascular homeostasis. Loss or impairment of vascular function can develop diseases, such as large bone defects, avascular necrosis, osteoporosis, osteoarthritis, and osteopetrosis. In this review, we summarize how vasculature controls bone development and homeostasis in normal and disease cases. A better understanding of this process will facilitate the development of novel disease treatments that promote bone regeneration and remodeling. Specifically, approaches based on tissue engineering components, such as stem cells and growth factors, have demonstrated the capacity to induce bone microvasculature regeneration and mineralization. This knowledge will have relevant clinical implications for the treatment of bone disorders by developing novel pharmaceutical approaches and bone grafts. Finally, the tissue engineering approaches incorporating vascular components may widely be applied to treat other organ diseases by enhancing their regeneration capacity.

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“…Shh gene delivery also inhibited radiation-induced cell senescence in the salivary glands of mice [115]. Some researchers found that compared with young mice (5 weeks old), the expression of Shh decreased in osteoblasts but increased in osteoclasts in old mice (60 weeks old), which is closely related to senile fracture healing [116], due to colocalization of Shh and Gli1 with osteogenic markers Runx2 and Osx, both of which can be observed during fracture healing [117]. Accumulated evidence indicated that resveratrol and two of its glycosides, polydatin and THSG, could activate the Shh pathway [75][76][77] and delay cell senescence [118][119][120][121][122].…”

Section: Notch/jaggedmentioning

confidence: 99%

Effect of Active Ingredients of Chinese Herbal Medicine on the Rejuvenation of Healthy Aging: Focus on Stem Cells

Wang

Ling

2020

Evidence-Based Complementary and Alternative Medicine

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Stem cells (SCs) are special types of cells with the ability of self-renewal and multidirectional differentiation. As the organism ages, the ability to maintain homeostasis and regeneration deteriorates and the number and activity of stem cells decline. Theoretically, the restoration of stem cells might reverse aging. However, due to their own aging, donor-derived immune rejection, and difficulties in stem cell differentiation control, a series of problems need to be solved to realize the potential for clinical application of stem cells. Chinese herbal medicine is a nature drug library which is suitable for the long-term treatment of aging-related diseases. Modern pharmacological studies have revealed that many active ingredients of Chinese herbal medicines with the effect of promoting stem cells growth and differentiation mainly belong to “reinforcing herbs.” In recent years, exploration of natural active ingredients from Chinese herbal medicines for delaying aging, improving the stem cell microenvironment, and promoting the proliferation and differentiation of endogenous stem cells has attracted substantial attention. This article will focus on active ingredients from Chinese herbs-mediated differentiation of stem cells into particular cell type, like neural cells, endothelial cells, cardiomyocytes, and osteoblasts. We will also discuss the effects of these small molecules on Wnt, Sonic Hedgehog, Notch, eNOS-cGMP, and MAP kinase signal transduction pathways, as well as reveal the role of estrogen receptor α and PPAR γ on selectively promoting or inhibiting stem cells differentiation. This review will provide new insights into the health aging strategies of active ingredients in Chinese herbal medicine in regenerative medicine.

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Sonic Hedgehog Regulates Bone Fracture Healing

Cited by 27 publications

References 24 publications

Effects of Strontium-Doped β-Tricalcium Scaffold on Longitudinal Nuclear Factor-Kappa Beta and Vascular Endothelial Growth Factor Receptor-2 Promoter Activities during Healing in a Murine Critical-Size Bone Defect Model

Effects of Strontium-Doped β-Tricalcium Scaffold on Longitudinal Nuclear Factor-Kappa Beta and Vascular Endothelial Growth Factor Receptor-2 Promoter Activities during Healing in a Murine Critical-Size Bone Defect Model

Bone Microvasculature: Stimulus for Tissue Function and Regeneration

Effect of Active Ingredients of Chinese Herbal Medicine on the Rejuvenation of Healthy Aging: Focus on Stem Cells

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