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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 ameliorates symptoms in a mouse model of collagen-induced arthritis (CIA). As described in “Methods”, arthritis was induced by immunization with collagen. From 10 days after the second immunization, mice were treated with oral HM71224, dexamethasone (Dexa), or vehicle (Veh). Compared with vehicle, treatment with HM71224 led to dose-dependent improvements in the clinical arthritis score (a) and body weight (b). c HM71224 reduced serum IL-6 (left), and anti-type II collagen (middle) and total IgG levels (right). d The bone erosion was assessed on a hematoxylin and eosin section. HM71224 treatment reduced the degree of bone erosion. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. CIA mice treated with vehicle. Ctrl (healthy) control
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Fig6: HM71224 ameliorates symptoms in a mouse model of collagen-induced arthritis (CIA). As described in “Methods”, arthritis was induced by immunization with collagen. From 10 days after the second immunization, mice were treated with oral HM71224, dexamethasone (Dexa), or vehicle (Veh). Compared with vehicle, treatment with HM71224 led to dose-dependent improvements in the clinical arthritis score (a) and body weight (b). c HM71224 reduced serum IL-6 (left), and anti-type II collagen (middle) and total IgG levels (right). d The bone erosion was assessed on a hematoxylin and eosin section. HM71224 treatment reduced the degree of bone erosion. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. CIA mice treated with vehicle. Ctrl (healthy) control

Mentions: Finally, we explored whether HM71224 could ameliorate the signs and symptoms of experimental arthritis. Mice treated with HM71224 had lower arthritis scores than untreated CIA mice (P < 0.05 at 10 mg/kg and P < 0.01 at 30 mg/kg). The efficacy of HM71224 at 10 mg/kg and 30 mg/kg was comparable with that of dexamethasone at 0.2 mg/kg (Fig. 6a). HM71224 at a dose of 3 mg/kg or higher prevented weight loss (Fig. 6b) (Additional file 1: Table S2). In addition, serum IL-6 levels and the levels of circulating anti-collagen antibodies were significantly lower in the HM71224 group than in the untreated group. The total IgG level tended to be lower after HM71224 treatment (Fig. 6c). HM71224 markedly reduced erosive bone changes and prevented bone loss (Fig. 6d).Fig. 6


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 ameliorates symptoms in a mouse model of collagen-induced arthritis (CIA). As described in “Methods”, arthritis was induced by immunization with collagen. From 10 days after the second immunization, mice were treated with oral HM71224, dexamethasone (Dexa), or vehicle (Veh). Compared with vehicle, treatment with HM71224 led to dose-dependent improvements in the clinical arthritis score (a) and body weight (b). c HM71224 reduced serum IL-6 (left), and anti-type II collagen (middle) and total IgG levels (right). d The bone erosion was assessed on a hematoxylin and eosin section. HM71224 treatment reduced the degree of bone erosion. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. CIA mice treated with vehicle. Ctrl (healthy) control
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: HM71224 ameliorates symptoms in a mouse model of collagen-induced arthritis (CIA). As described in “Methods”, arthritis was induced by immunization with collagen. From 10 days after the second immunization, mice were treated with oral HM71224, dexamethasone (Dexa), or vehicle (Veh). Compared with vehicle, treatment with HM71224 led to dose-dependent improvements in the clinical arthritis score (a) and body weight (b). c HM71224 reduced serum IL-6 (left), and anti-type II collagen (middle) and total IgG levels (right). d The bone erosion was assessed on a hematoxylin and eosin section. HM71224 treatment reduced the degree of bone erosion. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. CIA mice treated with vehicle. Ctrl (healthy) control
Mentions: Finally, we explored whether HM71224 could ameliorate the signs and symptoms of experimental arthritis. Mice treated with HM71224 had lower arthritis scores than untreated CIA mice (P < 0.05 at 10 mg/kg and P < 0.01 at 30 mg/kg). The efficacy of HM71224 at 10 mg/kg and 30 mg/kg was comparable with that of dexamethasone at 0.2 mg/kg (Fig. 6a). HM71224 at a dose of 3 mg/kg or higher prevented weight loss (Fig. 6b) (Additional file 1: Table S2). In addition, serum IL-6 levels and the levels of circulating anti-collagen antibodies were significantly lower in the HM71224 group than in the untreated group. The total IgG level tended to be lower after HM71224 treatment (Fig. 6c). HM71224 markedly reduced erosive bone changes and prevented bone loss (Fig. 6d).Fig. 6

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