Characterization of Mesenchymal Stem Cells Derived from Bisphosphonate-Related Osteonecrosis of the Jaw Patients’ Gingiva

Li, Mengyu; Wang, Jiajia; Yu, Yinglan; Zhou, Yuqiong; Shi, Yueqi; Zhang, Wenjie; Son, Geehun; Ge, Jing; Zhao, Jun; Chen, Yang; Wang, Shaoyi

doi:10.1007/s12015-021-10241-8

Cited by 4 publications

(4 citation statements)

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“…In addition to the binding of crystal structures of complexes between ZOL and FPPS, our results provide a basis for exploring the biological effects of ZOL. BRONJ is a rare, but potentially serious, adverse event associated with high cumulative doses of antiresorptives (Li et al, 2021). ZOL is the most widely used antiresorptive agent, and it has the function of inhibiting osteoclast maturation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Structural insights into the binding of zoledronic acid with RANKL via computational simulations

Wang

Zhang²,

Ma³

et al. 2022

Front. Mol. Biosci.

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Zoledronic acid (ZOL) inhibits receptor activator of nuclear factor-κB ligand (RANKL) and reduces bone turnover. This plays an important role in the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Previous reports have shown that ZOL binds to the enzyme farnesyl pyrophosphate synthase (FPPS) to block its activity. However, the mechanism of action of ZOL and its interaction with RANKL is still unclear. In this study, we confirmed that ZOL significantly suppressed the bone remodeling in ZOL-treated rats, investigated whether ZOL could bind to RANKL and examined the interactions between these molecules at the atomic level. Surface plasmon resonance (SPR) assay was performed to validate that ZOL could directly bind to RANKL in a dose dependent manner, and the equilibrium constant was calculated (KD = 2.28 × 10−4 M). Then, we used molecular docking simulation to predict the binding site and analyze the binding characteristics of ZOL and RANKL. Through molecular dynamics simulation, we confirmed the stable binding between ZOL and RANKL and observed their dynamic interactions over time. Binding free energy calculations and its decomposition were conducted to obtain the binding free energy −70.67 ± 2.62 kJ/mol for the RANKL–ZOL complex. We identified the key residues of RANKL in the binding region, and these included Tyr217(A), Val277(A), Gly278(A), Val277(B), Gly278(B), and Tyr215(C). Taken together, our results demonstrated the direct interaction between ZOL and RANKL, indicating that the pharmacological action of ZOL might be closely related to RANKL. The design of novel small molecules targeting RANKL might reduce the occurrence of BRONJ.

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Section: Discussionmentioning

confidence: 99%

“…BRONJ is a rare, but potentially serious, adverse event associated with high cumulative doses of antiresorptives ( Li et al, 2021 ). ZOL is the most widely used antiresorptive agent, and it has the function of inhibiting osteoclast maturation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Structural insights into the binding of zoledronic acid with RANKL via computational simulations

Wang

Zhang²,

Ma³

et al. 2022

Front. Mol. Biosci.

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“…Gingival samples from MRONJ patients also displayed suppression of collagen expression and distribution in the lamina propria (Li et al, 2022).…”

Section: Histopathology Of Mronj In Humans and Mronj-like Lesions In ...mentioning

confidence: 98%

“…Gram‐positive bacterial species were found in six of seven specimens. Gingival samples from MRONJ patients also displayed suppression of collagen expression and distribution in the lamina propria (Li et al, 2022).…”

Section: Histopathology Of Mronj In Humans and Mronj‐like Lesions In ...mentioning

confidence: 99%

Medication‐related osteonecrosis of the jaw: A literature review and update

Kuroshima

Al-Omari

Sasaki

et al. 2022

Genesis

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Since the initial description of medication-related osteonecrosis of the jaw (MRONJ) almost two decades ago, the potential pathophysiology and risk factors have been elaborated on in many investigations and guidelines. However, the definitive pathophysiology based on scientific evidence remains lacking. Consequently, the optimal clinical treatment and prevention strategies for MRONJ have not been established.Despite their different mechanisms of action, many drugs, including bisphosphonates, denosumab, angiogenesis inhibitors, and other medications, have been reported to be associated with MRONJ lesions in cancer and osteoporosis patients. Importantly, MRONJ occurs predominantly in the jawbones and other craniofacial regions, but not in the appendicular skeleton. In this up-to-date review, the currently available information and theories regarding MRONJ are presented from both clinical and basic science perspectives. The definition and epidemiology of MRONJ, triggering medication, and histopathology are comprehensively summarized. The immunopathology and the

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