Bone is a complex tissue that contains various types of cells. There exist two major cell types responsible for bone remodeling are bone-resorbing osteoblasts and bone-forming osteoblasts. Besides, Bone turnover plays an important role in the normal homeostasis of the body skeleton. It is critical to design targeting up-regulated activation of osteoblasts for patients with rheumatoid arthritis (RA) by controlling osteolytic loss. Additionally, RANKL strongly induces the nuclear factor of activated T cells c1 (NFATc1). NFATc1 directly regulates some osteoclast-specific genes such as TRAP, calcitonin receptor, cathepsin K, β3 integrin, and OSCAR.
In this article, we will introduce a novel benzamide-linked small molecule, NDMC101.
NDMC101 is screened by salicylate-based derivatives which pharmaceutical composition for inhibiting osteoclast formation.
NDMC101 inhibits RANKL-induced osteoclast differentiation of bone marrow-derived macrophages (BMDMs) and RAW 264.7 cell. Additionally, It decreases RANKL-induced expression of the osteoclastogenic genes Nfatc1, Acp5, Ctsk, Oscar, Itgb3, and Dcstamp in BMDMs.
In collagen-induced arthritic DBA/1 J mice experiments.The mice are divided into four groups: (i) CIA; (ii) CIA plus vehicle; (iii) CIA plus NDMC101 (17.5 mg/kg) (iv) CIA plus NDMC101 (62.5 mg/kg).
male DBA/1 J mice receive intradermal injection of 100 μg of bovine type II collagen within complete Freund’s adjuvant. Then, two weeks later, the mice receive a booster intradermal injection of bovine type II collagen emulsified in incomplete
Freund’s adjuvant (1:1, v/v) into the base of the tail.
After the second immunization, the development of rheumatic symptoms appears approximately on day 22. Then, Arthritis develops proximately 3 weeks after the primary immunization with type II collagen.
NDMC101 significantly reduces the mean arthritic scores and paw swelling. Besides, the NDMC101-treated mice exhibit much less infiltration of inflammatory cells. And NDMC101 also reduces synovial hyperplasia, and the articular bone destruction in inflamed joints than in the vehicle-treated mice.
Cartilage destruction is assessed by toluidine blue staining. Oral gavage of NDMC101 at a dose of 62.5 mg/kg shows a significant reduction in cartilage loss compared with the control mice.
In conclusion, NDMC101 is a potent osteoclastogenesis inhibitor and inhibits osteoclast differentiation via down-regulation of NFATc1-modulated gene expression.
. Chia-Pi Cheng, et al. A benzamide-linked small molecule NDMC101 inhibits NFATc1 and NF-κB activity: a potential osteoclastogenesis inhibitor for experimental arthritis. J Clin Immunol. 2012 Aug;32(4):762-77.