Abstract
Abnormally elevated formation and activation of osteoclasts are primary causes for a majority of skeletal diseases. In this study, we found that KP-A159, a newly synthesized thiazolopyridine derivative, inhibited osteoclast differentiation and function in vitro, and inflammatory bone loss in vivo. KP-A159 did not cause a cytotoxic response in bone marrow macrophages (BMMs), but significantly inhibited the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). KP-A159 also dramatically inhibited the expression of marker genes related to osteoclast differentiation, including TRAP (Acp5), cathepsin K (Ctsk), dendritic cell-specific transmembrane protein (Dcstamp), matrix metallopeptidase 9 (Mmp9), and nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1). Moreover, actin ring and resorption pit formation were inhibited by KP-A159. Analysis of the signaling pathway involved showed that KP-A159 inhibited RANKL-induced activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase kinase1/2 (MEK1/2). In a mouse inflammatory bone loss model, KP-A159 significantly rescued lipopolysaccharide (LPS)-induced bone loss by suppressing osteoclast numbers. Therefore, KP-A159 targets osteoclasts, and may be a potential candidate compound for prevention and/or treatment of inflammatory bone loss.
Highlights
Osteoclasts are a specialized type of cells capable of resorbing bone, and arise from progenitors of the monocyte/macrophage lineage
RANKL binding to RANK leads to activation of mitogen-activated protein kinases (MAPKs), such as p38, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK); these in turn activate several transcription factors, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), and NFATc1, which induce the expression of osteoclast-specific genes [4,5]
These results indicate that KP-A159 dramatically suppresses the generation of osteoclast-like multinucleated cells (MNCs) from bone marrow macrophages (BMMs) without any cytotoxic effect
Summary
Osteoclasts are a specialized type of cells capable of resorbing bone, and arise from progenitors of the monocyte/macrophage lineage. RANKL binding to RANK leads to activation of mitogen-activated protein kinases (MAPKs), such as p38, ERK, and JNK; these in turn activate several transcription factors, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), and NFATc1, which induce the expression of osteoclast-specific genes [4,5]. Elevated formation and resorbing activity of osteoclasts induce disruption of the equilibrium between bone formation and resorption. Since the elaborate functions of both bone-forming osteoblasts and bone-resorbing osteoclasts play key roles in bone remodeling for the retention of bone density and quality, enhanced function of osteoclasts can give rise to various skeletal diseases, including osteoporosis, rheumatoid arthritis, and Paget’s disease [1,6,7]. Targeting or managing the enhanced formation and function of osteoclasts might be effective ways to prevent and remedy skeletal diseases
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