A benzamide-linked small molecule NDMC101 inhibits NFATc1 and NF-κB activity: A potential osteoclastogenesis inhibitor for experimental arthritis

Chia Pi Cheng, Hsu Shan Huang, Yu Chieh Hsu, Ming Jen Sheu, Deh Ming Chang

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose Using receptor activator of NF-γB ligand (RANKL) induced osteoclast differentiation on RAW264.7 as a screening tool; we synthesize and identify small-molecule inhibitors preserving immunomodulatory effects as therapeutics for rheumatoid arthritis. Methods Differentiation into osteoclast-like cells was examined by tartrate-resistant acid phosphatase (TRAP) staining and expression of osteoclast differentiation markers. Collageninduced arthritis (CIA) mice were administered test articles by gavages to assess its efficacy. Then clinical, histological, and biochemical parameters were assessed to determine the effects of N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide (NDMC101) on synovial inflammation and bone erosion by hematoxlin and eosin staining and Enzyme-linked immunosorbent assay (ELISA). Results NDMC101 markedly inhibited RANKL-induced formation of TRAP+ multinucleated cells in RAW264.7 and bone marrow macrophage cells (BMMs). Moreover, pit formation assay showed that NDMC101 significantly reduced the bone-resorbing activity of mature osteoclasts. In CIA mice, oral administration of NDMC101 reduced arthritic index and mitigated bone erosion. Serum TNF-a and IL-1β concentrations in these mice were decreased significantly at the higher dose of 62.5 mg/kg. Conclusions Screening of our chemical library, our findings suggest that NDMC101 inhibits osteoclastogenesis which also ameliorates paw swelling and inflammatory bone destruction. Its efficacy is associated with the inhibition of such transcription factors as NF-?B and NFATc1 as well as multiple protein kinases, including p38, ERK, and JNK. There results guarantee further clinical tests of NDMC101 for its therapeutic potential in the treatment of inflammationinduced bone diseases.

Original languageEnglish
Pages (from-to)762-777
Number of pages16
JournalJournal of Clinical Immunology
Volume32
Issue number4
DOIs
Publication statusPublished - Aug 2012
Externally publishedYes

Fingerprint

Experimental Arthritis
Osteogenesis
Osteoclasts
Arthritis
Staining and Labeling
Small Molecule Libraries
Bone and Bones
Osteitis
Bone Diseases
Differentiation Antigens
Therapeutic Uses
p38 Mitogen-Activated Protein Kinases
Eosine Yellowish-(YS)
benzamide
N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide
Interleukin-1
Bone Marrow Cells
Oral Administration
Rheumatoid Arthritis
Transcription Factors

Keywords

  • Collagen-induced arthritis
  • NFATc1
  • Osteoclast
  • Salicylic acid

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

A benzamide-linked small molecule NDMC101 inhibits NFATc1 and NF-κB activity : A potential osteoclastogenesis inhibitor for experimental arthritis. / Cheng, Chia Pi; Huang, Hsu Shan; Hsu, Yu Chieh; Sheu, Ming Jen; Chang, Deh Ming.

In: Journal of Clinical Immunology, Vol. 32, No. 4, 08.2012, p. 762-777.

Research output: Contribution to journalArticle

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abstract = "Purpose Using receptor activator of NF-γB ligand (RANKL) induced osteoclast differentiation on RAW264.7 as a screening tool; we synthesize and identify small-molecule inhibitors preserving immunomodulatory effects as therapeutics for rheumatoid arthritis. Methods Differentiation into osteoclast-like cells was examined by tartrate-resistant acid phosphatase (TRAP) staining and expression of osteoclast differentiation markers. Collageninduced arthritis (CIA) mice were administered test articles by gavages to assess its efficacy. Then clinical, histological, and biochemical parameters were assessed to determine the effects of N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide (NDMC101) on synovial inflammation and bone erosion by hematoxlin and eosin staining and Enzyme-linked immunosorbent assay (ELISA). Results NDMC101 markedly inhibited RANKL-induced formation of TRAP+ multinucleated cells in RAW264.7 and bone marrow macrophage cells (BMMs). Moreover, pit formation assay showed that NDMC101 significantly reduced the bone-resorbing activity of mature osteoclasts. In CIA mice, oral administration of NDMC101 reduced arthritic index and mitigated bone erosion. Serum TNF-a and IL-1β concentrations in these mice were decreased significantly at the higher dose of 62.5 mg/kg. Conclusions Screening of our chemical library, our findings suggest that NDMC101 inhibits osteoclastogenesis which also ameliorates paw swelling and inflammatory bone destruction. Its efficacy is associated with the inhibition of such transcription factors as NF-?B and NFATc1 as well as multiple protein kinases, including p38, ERK, and JNK. There results guarantee further clinical tests of NDMC101 for its therapeutic potential in the treatment of inflammationinduced bone diseases.",
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N2 - Purpose Using receptor activator of NF-γB ligand (RANKL) induced osteoclast differentiation on RAW264.7 as a screening tool; we synthesize and identify small-molecule inhibitors preserving immunomodulatory effects as therapeutics for rheumatoid arthritis. Methods Differentiation into osteoclast-like cells was examined by tartrate-resistant acid phosphatase (TRAP) staining and expression of osteoclast differentiation markers. Collageninduced arthritis (CIA) mice were administered test articles by gavages to assess its efficacy. Then clinical, histological, and biochemical parameters were assessed to determine the effects of N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide (NDMC101) on synovial inflammation and bone erosion by hematoxlin and eosin staining and Enzyme-linked immunosorbent assay (ELISA). Results NDMC101 markedly inhibited RANKL-induced formation of TRAP+ multinucleated cells in RAW264.7 and bone marrow macrophage cells (BMMs). Moreover, pit formation assay showed that NDMC101 significantly reduced the bone-resorbing activity of mature osteoclasts. In CIA mice, oral administration of NDMC101 reduced arthritic index and mitigated bone erosion. Serum TNF-a and IL-1β concentrations in these mice were decreased significantly at the higher dose of 62.5 mg/kg. Conclusions Screening of our chemical library, our findings suggest that NDMC101 inhibits osteoclastogenesis which also ameliorates paw swelling and inflammatory bone destruction. Its efficacy is associated with the inhibition of such transcription factors as NF-?B and NFATc1 as well as multiple protein kinases, including p38, ERK, and JNK. There results guarantee further clinical tests of NDMC101 for its therapeutic potential in the treatment of inflammationinduced bone diseases.

AB - Purpose Using receptor activator of NF-γB ligand (RANKL) induced osteoclast differentiation on RAW264.7 as a screening tool; we synthesize and identify small-molecule inhibitors preserving immunomodulatory effects as therapeutics for rheumatoid arthritis. Methods Differentiation into osteoclast-like cells was examined by tartrate-resistant acid phosphatase (TRAP) staining and expression of osteoclast differentiation markers. Collageninduced arthritis (CIA) mice were administered test articles by gavages to assess its efficacy. Then clinical, histological, and biochemical parameters were assessed to determine the effects of N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide (NDMC101) on synovial inflammation and bone erosion by hematoxlin and eosin staining and Enzyme-linked immunosorbent assay (ELISA). Results NDMC101 markedly inhibited RANKL-induced formation of TRAP+ multinucleated cells in RAW264.7 and bone marrow macrophage cells (BMMs). Moreover, pit formation assay showed that NDMC101 significantly reduced the bone-resorbing activity of mature osteoclasts. In CIA mice, oral administration of NDMC101 reduced arthritic index and mitigated bone erosion. Serum TNF-a and IL-1β concentrations in these mice were decreased significantly at the higher dose of 62.5 mg/kg. Conclusions Screening of our chemical library, our findings suggest that NDMC101 inhibits osteoclastogenesis which also ameliorates paw swelling and inflammatory bone destruction. Its efficacy is associated with the inhibition of such transcription factors as NF-?B and NFATc1 as well as multiple protein kinases, including p38, ERK, and JNK. There results guarantee further clinical tests of NDMC101 for its therapeutic potential in the treatment of inflammationinduced bone diseases.

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