Abstract
An abnormal increase in osteoclast differentiation and activation results in various bone-resorptive diseases, including periodontitis, rheumatoid arthritis, and osteoporosis. Chemical compounds containing pyrimidine ring have been shown to regulate a variety of biological processes. Therefore, in order to identify an antiresorptive agent, we synthesized a series of pyrimidine ring-containing chemical compounds, and found that OCLI-023 suppressed the differentiation and activation of osteoclasts in vitro. OCLI-023 directly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation of bone marrow macrophages into osteoclasts, without a cytotoxic response. OCLI-023 also downregulated the RANKL-induced mRNA expression of osteoclast markers as well as inhibited the formation of actin rings and resorption pits. OCLI-023 attenuated the RANKL-induced activation of c-Jun N-terminal kinase and nuclear factor kappa-light-chain-enhancer of activated B cell signaling pathways. In a mouse model of periodontitis, ligature induced an increase of distance between cementoenamel junction (CEJ) and alveolar bone crest (ABC) in the second molar, and OCLI-023 significantly reduced it. Histological analysis showed ligature-induced increase of osteoclast numbers was also significantly reduced by OCLI-023. These data demonstrated the inhibitory effect of OCLI-023 on osteoclast differentiation and activity of osteoclasts in vitro, as well as on ligature-induced bone loss in vivo, and OCLI-023 can be proposed as a novel anti-resorptive compound.
Highlights
Bones are responsible for supporting teeth and the whole body and repetitively undergo a resorption and formation cycle to maintain the quality and mass throughout the lifetime [1]
To elucidate whether OCLI-023 inhibits the RANKL-mediated osteoclast differentiation of bone marrow macrophages (BMMs), mouse BMMs stimulated with macrophage colony-stimulating factor (M-CSF) (10 ng/mL) and RANKL (20 ng/mL) were incubated with or without 1 μM or 5 μM OCLI-023
The number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) was reduced in a dose-dependent manner, and at 5 μM OCLI-023, the formation of MNCs was suppressed by 72.1% (p < 0.01) (Fig 1D)
Summary
Bones are responsible for supporting teeth and the whole body and repetitively undergo a resorption and formation cycle to maintain the quality and mass throughout the lifetime [1]. Osteoblasts, generated from mesenchymal stem cells, synthesize and mineralize the bone. OCLI-023 Suppresses Osteoclastogenesis and Periodontitis matrix, while osteoclasts are formed by the cellular fusion of monocyte/macrophage-lineage cells and resorb mineralized bone tissue [2, 3]. Accurate regulation of bone formation and bone resorption is a key factor affecting normal bone remodeling. Abnormal bone remodeling, caused by the disproportionately increased bone destruction, leads to various bone diseases, including periodontitis [2,3,4]. The reduction of osteoclast differentiation and/or resorbing activity could be an effective way to manage such bone diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
