Prolonged alendronate treatment prevents the decline in serum TGF-β1 levels and reduces cortical bone strength in long-term estrogen deficiency rat model

Jia, Junjing; Yao, Wei; Amugongo, Sarah; Shahnazari, Mohammad; Dai, Weiwei; Lay, Yu An E.; Olvera, Diana; Zimmermann, Elizabeth A.; Ritchie, Robert O.; Li, Chin Shang; Alliston, Tamara; Lane, Nancy E.

doi:10.1016/j.bone.2012.10.017

Cited by 16 publications

(12 citation statements)

References 74 publications

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“…Meanwhile, we showed that knockout of PAR-1 inhibited tumor growth, angiogenesis and osteoclastogenesis both in vitro and in vivo. Previous studies 13,38 have confirmed that osteoclastic destruction could release and activate TGF-b stored in bone matrix, which would further activate PAR-1 in GCTSCs, fueling the cycle (Fig. 6g).…”

Section: Discussionmentioning

confidence: 61%

TGF‐β induced PAR‐1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

Wang

Jiao

Zhang

et al. 2017

Intl Journal of Cancer

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Although protease activated receptor-1 (PAR-1) has been confirmed as an oncogene in many cancers, the role of PAR-1 in giant cell tumor (GCT) of bone has been rarely reported. The mechanism of PAR-1 in tumor-induced osteoclastogenesis still remains unclear. In the present study, we detected that PAR-1 was significantly upregulated in GCT of bone compared to normal tissues, while TGF-β was also overexpressed in GCT tissues and could promote the expression of PAR-1 in a dose and time dependent manner. Using the luciferase reporter assay, we found that two downstreams of TGF-β, Smad3 and Smad4, could activate the promoter of PAR-1, which might explain the mechanism of TGF-β induced PAR-1 expression. Meanwhile, PAR-1 was also overexpressed in microvesicles from stromal cells of GCT (GCTSCs), and might be transported from GCTSCs to monocytes through microvesicles. In addition, knockout of PAR-1 by TALENs in GCTSCs inhibited tumor growth, angiogenesis and osteoclastogenesis in GCT in vitro. Using the chick CAM models, we further showed that inhibition of PAR-1 suppressed tumor growth and giant cell formation in vivo. Using microarray assay, we detected a number of genes involved in osteoclastogenesis as the possible downstreams of PAR-1, which may partly explain the mechanism of PAR-1 in GCT. In brief, for the first time, these results reveal an upstream regulatory role of TGF-β in PAR-1 expression, and PAR-1 expression promotes tumor growth, angiogenesis and osteoclast differentiation in GCT of bone. Hence, PAR-1 represents a novel potential therapeutic target for GCT of bone.

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Section: Discussionmentioning

confidence: 61%

TGF‐β induced PAR‐1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

Wang

Jiao

Zhang

et al. 2017

Intl Journal of Cancer

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“…Another important point of this study was the choice of the TGF-β1 marker to accomplish the immunohistochemical evaluation. This marker is responsible for maintaining a constant bone mass, acting directly on the regulation of osteoblast differentiation and promoting polymorphonuclear cell chemotaxis, broblast proliferation, and collagen I synthesis (5). TGF-β1 is a physiological regulator of osteoblast differentiation and a key mediator of the coupling of osteoblast differentiation and osteoclastic bone resorption, which is required for skeletal homeostasis (26).…”

Section: -Discussionmentioning

confidence: 99%

“…Other studies had also proved the relation between them, suggesting that ALN acts directly on this marker, increasing its level (5, 6) A smaller dosage of ALN (1 mg/kg) contributed with less negative impact on the TGF-β1 marker compared to the higher dosage (3 mg/kg), as noted in this study. A study by Jei et al (5) concluded that prolonged reduction of bone turnover after alendronate treatment in female rats increased TGF-β1 production by bone marrow cells and periosteal osteoprogenitors. Table II.…”

Section: -Discussionmentioning

confidence: 99%

“…The use of ALN causes a decrease in osteoclastic activity without directly interfering in neoformation: the drug is quickly distributed to bones or excreted by kidneys (2,3). Alendronate acts directly on Transforming Grow Factor β-1 (TGF-β1) by increasing its amount, which induces osteogenesis and chondrogenesis, which in turn play an important role in cell growth, differentiation, and protein synthesis of the extracellular matrix (4)(5)(6).…”

Section: -Backgroundmentioning

confidence: 99%

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Effects of alendronate in bone repair: A study in rat femur fractures treated with plates and screws

Tiboni¹,

Weiss²,

Gerber³

et al. 2020

Preprint

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Background Alendronate (ALN) has direct action on bone metabolism, increasing osteogenesis and decreasing bone resorption. The study rated the effect of ALN on femoral fracture repair and the effect of different doses of the drug on the liver and kidneys. Methods Wistar rats were divided into groups: A1 (ALN 1 mg/kg), A2 (ALN 3 mg/kg), and C (saline solution). The drug/solution was applied intraperitoneally three times a week after femoral fracture until euthanasia 45 days later. Results Liver analysis from group A1 presented normal histological aspects, while hepatic steatosis was observed in group A2. In groups A1 and A2, kidneys showed amylocymile like cell degeneration. In femur bone callus, no difference was observed in collagens I and III or in number of trabeculae (p ≥ 0.05). Immunohistochemical evaluation showed positivity for the Transforming Grow Factor β-1 (TGFβ-1) marker in the control group, in spinal area and in small chondrocytes, but negativity for hypertrophy. In A1, an extensive area of cartilaginous expansion was observed, with positive hypertrophic TGFβ-1 cartilage, even in areas with bone matrix. A low positivity was observed in the medullar area, in contrast to the control. Group A2 presented a high number of chondroid matrices and a moderate number of TGFβ-1 cells, with little positivity in medullary area. Conclusions A dosage of ALN 1 mg/kg promotes cellular differentiation activity in the bone callus region, with mild damage in the liver and kidneys. A dosage of ALN 3 mg/kg became toxic without positive alterations in cell differentiation.

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“…TGF-b has direct effects on the regulation of osteoblast differentiation; its reduction in osteoblasts has been shown to expand bone mineral concentration and bone mass [8][9][10]. VEGF, a known promoter of angiogenesis, stimulates neovascularization and promotes fracture healing, and also regulates activity of osteoclasts and osteoblasts [11,12].…”

Section: Introductionmentioning

confidence: 99%

The effect of femoral nerve block on fracture healing via expressions of growth factors and β-catenin

Uslu

İrban

Gereli

et al. 2016

Folia Histochem Cytobiol.

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Introduction. Many patients of all ages are admitted to hospital due to bone fractures. The etiology of fracture has a very wide spectrum, ranging from motor accidents to pathological conditions such as tumors, osteoporosis, and others. Bone fracture healing is a well-programmed and well-organized process, but is also long and intractable. The outcome of this process is therefore affected by many factors, such as the patient's age, ethnicity, nutritional status, and extent of the fracture. At present, regional analgesic techniques are frequently applied in order to avoid the complications of systemic opioid administration, central block applications. Femoral block is one of the regional analgesic techniques frequently applied by anesthesiologists when the lower extremities are involved. In this study, we evaluated the effect of femoral nerve block on the healing of an experimental non-stabilized femur fracture via expression of TGF-b, VEGF, and b-catenin and bone histomorphometry in rats. Material and methods. In the control group, only the femoral fracture was performed and the bone was not fixated, similarly as in other groups. In the One-Day Block group, a one-time femoral nerve block was applied after the femoral fracture. In the Three-Day Block group, a daily femoral nerve block was performed for three days after the femoral fracture. On Days 4, 7, and 13, femurs were excised. The bone sections were stained with hematoxylin-eosin to evaluate bone tissue and Safranin O to assess callus tissue, cartilaginous tissue, and new bone areas. TGF-b, VEGF, and b-catenin were assessed by immunohistochemistry. Results. Histomorphometric analysis revealed that femoral block application had a positive impact on bone healing. TGF-b expression in the One-Day and Three-Day Block Groups was significantly higher than in the control group at all times, as was also the case with VEGF expression. On day 13, b-catenin expression was significantly higher in the Three-Day Block group than the others. Conclusions. The results of the study suggests that the applications of a femoral nerve block for perioperative analgesia, for either one day or three days, resulted in better and more rapid bone healing. (Folia Histochemica et Cytobiologica 2016, Vol. 54, No. 3, 151-158)

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Prolonged alendronate treatment prevents the decline in serum TGF-β1 levels and reduces cortical bone strength in long-term estrogen deficiency rat model

Cited by 16 publications

References 74 publications

TGF‐β induced PAR‐1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

TGF‐β induced PAR‐1 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone

Effects of alendronate in bone repair: A study in rat femur fractures treated with plates and screws

The effect of femoral nerve block on fracture healing via expressions of growth factors and β-catenin

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