A novel Bruton's tyrosine kinase inhibitor, acalabrutinib, suppresses osteoclast differentiation and Porphyromonas gingivalis lipopolysaccharide‐induced alveolar bone resorption

Abstract

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 κB 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‐κB. 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.

Role of inflammasomes in the pathogenesis of periodontal disease and therapeutics

“…Recently, another BTK inhibitor, acalabrutinib (ACP-196), has been evaluated for its potential to prevent alveolar bone loss in experimental periodontitis. 157 In this study, mice that received intragingival injections of P. gingivalis-derived lipopolysaccharide were also given intraperitoneal injection of acalabrutinib (0.5 mg/kg on days 1, 4 and 7 postligature placement). The results showed that BTK inhibitor ACP-196 altered osteoclastogenesis and significantly decreased alveolar bone loss by approximately 50% compared with controls.…”

Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets – Beyond B Lymphocytes

“…BTK is expressed in osteoclasts and is essential for RANKL-induced osteoclast differentiation (Lee et al, 2008). Both ibrutinib and acalabrutinib potently inhibit RANKL-induced osteoclast differentiation in in vitro cultured bone marrow-derived monocytes/macrophages (BMMs) or RAW264.7 cells via the RANK-BTK-PLCγ1/γ2-NF-ATc1 pathway (Shinohara et al, 2014;Pokhrel et al, 2019;Liu et al, 2021). Acalabrutinib also inhibits LPS-induced osteoclast differentiation from RANKL-primed osteoclast precursors via the TLR4-BTK-NF-ATc1/c-Fos pathway (Pokhrel et al, 2019).…”

“…Both ibrutinib and acalabrutinib potently inhibit RANKL-induced osteoclast differentiation in in vitro cultured bone marrow-derived monocytes/macrophages (BMMs) or RAW264.7 cells via the RANK-BTK-PLCγ1/γ2-NF-ATc1 pathway (Shinohara et al, 2014;Pokhrel et al, 2019;Liu et al, 2021). Acalabrutinib also inhibits LPS-induced osteoclast differentiation from RANKL-primed osteoclast precursors via the TLR4-BTK-NF-ATc1/c-Fos pathway (Pokhrel et al, 2019). Both ibrutinib and acalabrutinib can significantly reduce the bone-resorbing activities of osteoclasts following treatment with RANKL and M-CSF (Shinohara et al, 2014;Pokhrel et al, 2019).…”

“…Acalabrutinib also inhibits LPS-induced osteoclast differentiation from RANKL-primed osteoclast precursors via the TLR4-BTK-NF-ATc1/c-Fos pathway (Pokhrel et al, 2019). Both ibrutinib and acalabrutinib can significantly reduce the bone-resorbing activities of osteoclasts following treatment with RANKL and M-CSF (Shinohara et al, 2014;Pokhrel et al, 2019). Interestingly, reduction in resorption activities of osteoblasts by ibrutinib is mediated through suppression of the expression of Src, Ptk2, Ptk2b and Talin 1 via an NF-ATc1-independent mechanism (Shinohara et al, 2014).…”

The Inflammasomes: A confounding chapter in Periodontics

“…65 The BTK inhibitor ibrutinib (PCI-32765, Imbruvica) is a FDAapproved drug for the treatment of various B cell cancers. Recently, another BTK inhibitor, acalabrutinib (ACP-196), has shown to prevent alveolar bone loss 66 indicating its possible role in treating periodontal diseases. 3.…”