Zoledronate inhibits receptor activator of nuclear factor kappa-B ligand-induced osteoclast differentiation via suppression of expression of nuclear factor of activated T-cell c1 and carbonic anhydrase 2
| Autor: | Kazumi Kubozono, Nobuyuki Kamata, Takako Naruse, Takayuki Nakagawa, Kouji Ohta, Masaaki Takechi, Yoko Ishida |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
musculoskeletal diseases
medicine.medical_specialty Cellular differentiation Acid Phosphatase Gene Expression Osteoclasts Biology Real-Time Polymerase Chain Reaction Zoledronic Acid Mice Osteoclast Internal medicine Gene expression medicine Animals RNA Messenger General Dentistry Carbonic Anhydrases Diphosphonates NFATC Transcription Factors Activator (genetics) Tartrate-Resistant Acid Phosphatase RANK Ligand Imidazoles Cell Differentiation Cell Biology General Medicine Microarray Analysis Isoenzymes medicine.anatomical_structure Endocrinology Denosumab Otorhinolaryngology RANKL Cancer research biology.protein Signal transduction Diterpenes medicine.drug Signal Transduction |
| Zdroj: | Archives of oral biology. 60(4) |
| ISSN: | 1879-1506 |
| Popis: | Bisphosphonates (BPs) are widely used in the prevention of skeletal-related events (SRE), including osteoporosis, skeletal metastases of malignant tumours, and multiple myeloma. Osteonecrosis of the jaw (ONJ) is frequently reported as a major adverse effect induced by BP treatment. The receptor activator of the nuclear factor kappa-B ligand (RANKL) inhibitor, denosumab, has recently been used to prevent SRE, but the frequency of ONJ induced by denosumab is similar to that by BPs. This finding suggests that the inhibition of RANKL-mediated osteoclastogenesis may have a close relationship with the occurrence of ONJ. We therefore investigated the expression status of RANKL-inducible genes in zoledronate-treated mouse osteoclast precursor cells. The molecular targets of zoledronate in the RANKL signal pathway and additional factors associated with osteoclastogenesis were analysed by genome-wide screening. Microarray analysis identified that among 31 genes on 44 entities of RANKL-inducible genes, the mRNA expression level of two genes, i.e., nuclear factor of activated T-cells c1 (NFATc1) and carbonic anhydrase 2 (CAII), was decreased in zoledronate-treated cells. Subsequent analyses verified that these two genes were significantly silenced by zoledronate treatment and that their expression was restored following inhibition of zoledronate action by geranylgeraniol. Zoledronate inhibited RANKL-induced osteoclast differentiation by suppression of NFATc1 and CAII gene expression. Our results suggest that these genes might be common targets for zoledronate and denosumab in the mechanism underlying RANKL-induced osteoclast differentiation. A clear understanding of the common molecular mechanisms of bone-remodelling agents is thus essential for prevention of ONJ. |
| Databáze: | OpenAIRE |
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