Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30956999.
- Also identified by DOI 10.1016/j.bonr.2019.100201 and PMC identifier 6431727.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Osteoclasts are responsible for bone erosion in osteoporosis and rheumatoid arthritis (RA). Both Btk and Tec kinases have essential functions in osteoclast differentiation. Tirabrutinib is a highly potent and dual oral Btk/Tec inhibitor with an IC<sub>50</sub> in the nmol/L range and significantly inhibits the M-CSF and RANKL-driven osteoclast differentiation. It was hypothesized that the <i>in vitro</i> activity of tirabrutinib could be demonstrated in mice bone resorption model. The RANKL model studies show that tirabrutinib significantly suppressed bone loss with the inhibition of serum TRAPCP5b and urinary CTX-1. Bone Mineral Density (BMD) loss in tirabrutinib-treated mice was 55% (<i>P</i> < .05), 87% (<i>P</i> < .001) and 88% (<i>P</i> < .001) for the 3, 10 and 30 mg/kg dose groups respectively. Btk and Tec are required for osteoclast differentiation and activation based on the genetic evidence obtained from Btk and Tec double deficient mice. Tirabrutinib may be a novel therapeutic target for bone diseases, such as osteoporosis and RA.