Research Article: OCLI-023, a Novel Pyrimidine Compound, Suppresses Osteoclastogenesis In Vitro and Alveolar Bone Resorption In Vivo

Date Published: January 13, 2017

Publisher: Public Library of Science

Author(s): Hye Jung Ihn, Taeho Lee, Ju Ang Kim, Doohyun Lee, Nam Doo Kim, Hong-In Shin, Yong Chul Bae, Eui Kyun Park, Dominique Heymann.


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.

Partial Text

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 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 [2–4]. Therefore, the reduction of osteoclast differentiation and/or resorbing activity could be an effective way to manage such bone diseases.

Anti-resorptive therapeutic agents including bisphosphonates can help prevent or slow the progression of skeletal diseases [21]. In spite of their beneficial effects, these medications can trigger various side effects, such as gastrointestinal problems and hypocalcemia [21, 22]. Hence, there have been extensive efforts to develop alternative medicines that can inhibit both osteoclast differentiation and the resorbing function of osteoclasts, without triggering any undesirable adverse events. In this study, we found that OCLI-023, a newly synthesized pyrimidine derivative, significantly inhibited the RANKL-mediated osteoclast differentiation in BMMs, as well as bone resorption of mature osteoclasts, by affecting the NF-κB and JNK signaling pathways. In addition, OCLI-023 suppressed alveolar bone loss induced by ligature in an in vivo model.




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