Magic™ Anti-NFATC1 monoclonal antibody

Bone remodeling is critical to maintain the quality of bone tissues and to heal bone tissue injury. Osteoclasts and osteoblasts are special types of cells involved in this event. In particular, the resorption activity of mature osteoclasts is required for the formation of new bones. Human small leucine zipper protein (sLZIP) is known to induce the osteoblast differentiation of mesenchymal stem cells. However, the roles of sLZIP in osteoclast differentiation and bone remodeling have not been explored. In this study, we investigated the roles of sLZIP in regulating osteoclast formation and in the bone remodeling process using sLZIP transgenic (TG) mice. Tibiae from sLZIP TG mice contained more osteoclasts than those from wild type (WT) mice. Bone marrow-derived macrophages (BMM) from sLZIP TG mice showed increased differentiation into osteoclasts compared with BMM from WT mice. sLZIP bound to the promotor and induced the expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and its target osteoclastogenic genes. To understand the role of sLZIP in bone remodeling, a bone-defect model was generated. Results of micro-CT scanning and histologic analysis demonstrated that sLZIP TG mice have faster bone formation during healing compared with WT mice. Notably, the soft callus around the defect area was replaced faster by hard callus in sLZIP TG mice than in WT mice. These findings suggest that sLZIP promotes osteoclast differentiation and plays an important role in bone remodeling.

Background Periodontitis is not only one of the most prevalent inflammatory diseases among adults, but also commonly linked to numerous systemic conditions including cardiovascular diseases, stroke, and diabetes. Although osteoclasts are responsible for the alveolar bone resorption during periodontitis pathogenesis, the development of pharmacologic strategies targeting these cells has not been vastly fruitful. Methods Bone marrow macrophages were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) to examine the direct effect of acalabrutinib on osteoclastogenesis. Ca2+ oscillation and nuclear localization of NFATc1 in osteoclast precursors were examined to determine the precise molecular mechanism. LPS-induced alveolar bone loss model was employed for studying effect in in vivo bone resorption. Results Acalabrutinib directly inhibited RANKL and LPS-induced in vitro osteoclast differentiation. In addition, acalabrutinib inhibited RANKL-induced phosphorylation of mitogen-activated protein kinases and reduced the expression of NF-kappa B. The inhibitory mechanism involved suppression of Ca2+ oscillation in osteoclast precursors resulting in the decreased NFATc1 expression and nuclear localization, which is a crucial prerequisite for osteoclastogenesis. The administration of acalabrutinib significantly reduced P. gingivalis lipopolysaccharide-induced alveolar bone erosion in mice. Conclusion These data indicate that acalabrutinib is an effective inhibitor of osteoclastogenesis both in vitro and in vivo, with a potential for a novel strategy against bone destruction by periodontitis.