Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts

Zafar, Sobia; Coates, Dawn; Cullinan, M. P.; Drummond, Bernadette; Milne, Trudy; Seymour, G. J.

doi:10.1007/s00784-015-1706-y

Cited by 39 publications

(59 citation statements)

References 44 publications

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“…And the results of raised CTX‐1 and TRACP 5b concentration confirmed the promoted osteoclast activity. The osteoclast was commonly reported to be inhibited in a BRONJ lesion; however, it was promoted in the current study. The counterintuitive result may be explained as follows: BPs were deposited in the area which has a high bone turnover and metabolism rates like mandible where BPs were resorbed by osteoclast and interfere with the resorptive capacity of osteoclasts.…”

Section: Discussionmentioning

confidence: 54%

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The effects of icariin on wound healing of extraction sites with administration of zoledronic and dexamethasone: A rat model study

Liu

Mattheos

et al. 2017

J Oral Pathology Medicine

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Section: Discussionmentioning

confidence: 54%

“…The use of BPs has improved life quality of patients who suffered from bone‐related diseases, but it adds risk to the BRONJ . BRONJ is diagnosed when patients receiving current or previous BPs treatment show bone exposure in the maxillofacial region that has persisted for more than 8 weeks and with no history of radiotherapy to the jaws .…”

Section: Discussionmentioning

confidence: 99%

The effects of icariin on wound healing of extraction sites with administration of zoledronic and dexamethasone: A rat model study

Liu

Mattheos

et al. 2017

J Oral Pathology Medicine

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“…The present study investigated the effects of 30 µM ZA alone, and with 50 µM GGOH as a potential reversal agent, on angiogenic gene expression in human osteoclasts derived from the monocyte fraction of peripheral blood. Currently, there have been only a limited number of investigations into the effects of bisphosphonates on gene expression using cell culture models [8,9,15,16]. Nakagawa et al (2015) carried out a microarray analysis to identify the molecular targets of ZA in the RANKL signaling pathway and factors associated with osteoclastogenesis using osteoclast precursor cells (purchased from the Primary Cell Co., Ltd. Sapporo, Japan) [17].…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of bone remodeling is thought to lead to the accumulation of areas of microdamage resulting in reduced mechanical strength and ultimately to areas of bone necrosis [5,6]. The most commonly accepted cellular target for bisphosphonates is osteoclasts and evidence has suggested an important regulatory mechanism for nitrogen-containing bisphosphonates is to inhibit enzymes of the mevalonate pathway (MVP) [6][7][8][9]. Inhibition of specific enzymes of the MVP results in alterations to the process of protein prenylation, which is required for the post-translational maturation of a family of proteins including the small GTP-binding proteins (Ras, Rho, Rac, and Rab).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, Zafar et al (2014Zafar et al ( , 2016 showed that ZA can alter the proliferation, migration and angiogenic gene expression of primary human gingival fibroblasts and primary human alveolar osteoblasts [8,9]. Subsequently, they showed that the replenishment of the MVP by geranylgeraniol (GGOH) was able to partially rescue angiogenic gene expression after ZA treatment.…”

Section: Introductionmentioning

confidence: 99%

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Effects of zoledronic acid and geranylgeraniol on angiogenic gene expression in primary human osteoclasts

et al. 2020

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Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious complication associated with bisphosphonate treatment. Zoledronic acid (ZA) is a commonly used bisphosphonate due to its effectiveness in increasing bone density and reducing skeletal events, with evidence that it alters angiogenesis. Replacement of the mevalonate pathway using geranylgeraniol (GGOH) was studied to determine the effects of ZA on angiogenic gene expression in primary human osteoclasts. Osteoclast cultures were generated from peripheral blood mononuclear cells of three patients using the peripheral blood mononuclear cell isolation. These cells were phenotyped by phase-contrast microscopy, tartrate-resistant acid phosphatase staining, and pit assays. Primary osteoclasts were found to express a number of key angiogenic molecules at very high levels. Gene expression levels for 84 human angiogenic factors were determined using PCR arrays. Three genes with significant fold regulation (FR) in response to ZA were as follows: tumor necrosis factor (FR = +2.57, P = 0.050), CXCL9 (FR = +39.48, P = 0.028), and CXCL10 (FR = +18.52, P = 0.0009). The co-addition of geranylgeraniol with ZA resulted in the significant down-regulation of these three genes along with CCL2, TGFBR1, ENG, and CXCL1. GGOH reversed the gene changes induced by ZA and may offer a promising treatment for BRONJ.

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Wound healing protein profiles in the postoperative exudate of bisphosphonate-related osteonecrosis of mandible

Kim

Cho

et al. 2017

Eur Arch Otorhinolaryngol

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Recurrent bacterial infections in cases of bisphosphonate-related osteonecrosis of jaw (BRONJ) frequently occur. Therefore, BRONJ are usually treated by radical saucerization followed by intensive antibiotic medications without bisphosphonate therapy. The postoperative exudate (POE) from BRONJ lesions may directly indicate the inflammatory status of osteomyelitis in patients, but so far, the POE has rarely been examined for its expression of various cytokines and wound healing proteins. A total of 27 cases of BRONJ, which involved the mandible, were selected and their individual POE collected 6 h, 1 day, and 2 days after surgical intervention was analyzed by immunoprecipitation high performance liquid chromatography (IP-HPLC). The different protein expressions in the BRONJ POE were compared with findings from ten cases of chronic mandibular osteomyelitis (CMO) exudate as the control group. For the protein expressions for inflammation, osteogenesis, and angiogenesis, in the 6 h POE sample, the BRONJ exudate exhibited more expression of IL-10, IL-28, OPG, and osteocalcin, but less expression of TNFα and LL-37 than the control. In the 1 day POE sample, the BRONJ exudate showed more expression of TNFα, IL-6, 8, 12, 28, α1-antitrypsin, VEGF-A, and VEGF-C, but less expression of CD68, lysozyme, bFGF, RANKL, bFGF, and ALP than the control. In the 2 day POE sample, the BRONJ exudate consistently showed more expression of LL-37, β-defensin-1, and VEGF-A than the control. The present BRONJ POE revealed the rapid progress of bony wound healing through increased molecular signaling for inflammation, angiogenesis, and osteogenesis compared to the control. Therefore, it was suggested that the POE obtained from the postoperative bony lesions should be collected and analyzed by the IP-HPLC method to predict the prognosis of seriously complicated inflammatory bony diseases such as BRONJ.

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Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts

Abstract: The results suggest that GGOH could be used as a possible therapeutic/preventive strategy for BRONJ.

Cited by 39 publications

References 44 publications

The effects of icariin on wound healing of extraction sites with administration of zoledronic and dexamethasone: A rat model study

The effects of icariin on wound healing of extraction sites with administration of zoledronic and dexamethasone: A rat model study

Effects of zoledronic acid and geranylgeraniol on angiogenic gene expression in primary human osteoclasts

Wound healing protein profiles in the postoperative exudate of bisphosphonate-related osteonecrosis of mandible

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