Limits...
HM71224, a novel Bruton's tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis.

Park JK, Byun JY, Park JA, Kim YY, Lee YJ, Oh JI, Jang SY, Kim YH, Song YW, Son J, Suh KH, Lee YM, Lee EB - Arthritis Res. Ther. (2016)

Bottom Line: The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation.Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes.Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehank-no Chongno-gu, Seoul, 03080, Korea.

ABSTRACT

Background: Bruton's tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis.

Methods: The kinase inhibition profile of HM71224 was analyzed. The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation. The in vivo effects of HM71224 were investigated in a mouse model of collagen-induced arthritis (CIA).

Results: HM71224 irreversibly bound to and inhibited Btk (IC50 = 1.95 nM). The compound also inhibited the phosphorylation of Btk and its downstream molecules such as PLCγ2, in activated Ramos B lymphoma cells and primary human B cells in a dose-dependent manner. Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes. Finally, HM71224 improved experimental arthritis and prevented joint destruction in a murine model of CIA.

Conclusions: HM71224 inhibits Btk in B cells and monocytes and ameliorates experimental arthritis in a mouse model. Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.

No MeSH data available.


Related in: MedlinePlus

HM71224 inhibits osteoclastogenesis. a Representative images of osteoclastogenesis. Human CD14+ monocytes were cultured with the indicated concentrations of HM71224 during osteoclast differentiation (magnification × 100). b Dose-dependent inhibition of tartrate resistant alkaline phosphatase (TRAP)+ cells by HM71224. *P < 0.05 and **P < 0.01 vs. no treatment. MNGs is multinucleated giant cells
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4835877&req=5

Fig5: HM71224 inhibits osteoclastogenesis. a Representative images of osteoclastogenesis. Human CD14+ monocytes were cultured with the indicated concentrations of HM71224 during osteoclast differentiation (magnification × 100). b Dose-dependent inhibition of tartrate resistant alkaline phosphatase (TRAP)+ cells by HM71224. *P < 0.05 and **P < 0.01 vs. no treatment. MNGs is multinucleated giant cells

Mentions: Osteoclasts were generated from human CD14+ cells. Numerous TRAP+ osteoclasts were generated in the absence of HM71224; these cells were able resorb the bone matrix and form pits. HM71224 inhibited osteoclast formation in a dose-dependent manner (Fig. 5). However, approximately 50 % of inhibition was reached at 1000 nM HM71224. Similarly, HM71224 inhibited osteoclast formation from murine BMMs (Additional file 1: Figure S4).Fig. 5


HM71224, a novel Bruton's tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis.

Park JK, Byun JY, Park JA, Kim YY, Lee YJ, Oh JI, Jang SY, Kim YH, Song YW, Son J, Suh KH, Lee YM, Lee EB - Arthritis Res. Ther. (2016)

HM71224 inhibits osteoclastogenesis. a Representative images of osteoclastogenesis. Human CD14+ monocytes were cultured with the indicated concentrations of HM71224 during osteoclast differentiation (magnification × 100). b Dose-dependent inhibition of tartrate resistant alkaline phosphatase (TRAP)+ cells by HM71224. *P < 0.05 and **P < 0.01 vs. no treatment. MNGs is multinucleated giant cells
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835877&req=5

Fig5: HM71224 inhibits osteoclastogenesis. a Representative images of osteoclastogenesis. Human CD14+ monocytes were cultured with the indicated concentrations of HM71224 during osteoclast differentiation (magnification × 100). b Dose-dependent inhibition of tartrate resistant alkaline phosphatase (TRAP)+ cells by HM71224. *P < 0.05 and **P < 0.01 vs. no treatment. MNGs is multinucleated giant cells
Mentions: Osteoclasts were generated from human CD14+ cells. Numerous TRAP+ osteoclasts were generated in the absence of HM71224; these cells were able resorb the bone matrix and form pits. HM71224 inhibited osteoclast formation in a dose-dependent manner (Fig. 5). However, approximately 50 % of inhibition was reached at 1000 nM HM71224. Similarly, HM71224 inhibited osteoclast formation from murine BMMs (Additional file 1: Figure S4).Fig. 5

Bottom Line: The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation.Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes.Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehank-no Chongno-gu, Seoul, 03080, Korea.

ABSTRACT

Background: Bruton's tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis.

Methods: The kinase inhibition profile of HM71224 was analyzed. The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation. The in vivo effects of HM71224 were investigated in a mouse model of collagen-induced arthritis (CIA).

Results: HM71224 irreversibly bound to and inhibited Btk (IC50 = 1.95 nM). The compound also inhibited the phosphorylation of Btk and its downstream molecules such as PLCγ2, in activated Ramos B lymphoma cells and primary human B cells in a dose-dependent manner. Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes. Finally, HM71224 improved experimental arthritis and prevented joint destruction in a murine model of CIA.

Conclusions: HM71224 inhibits Btk in B cells and monocytes and ameliorates experimental arthritis in a mouse model. Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.

No MeSH data available.


Related in: MedlinePlus