School of Pharmacy, Jeonbuk National University, Jeonju, 561-756, South Korea.
College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, South Korea.
Eur J Pharmacol. 2020 Sep 15;883:173305. doi: 10.1016/j.ejphar.2020.173305. Epub 2020 Jul 14.
An imbalance between bone resorption and bone formation leads to several kinds of bone diseases such as rheumatoid arthritis, osteoporosis and Paget's disease. The imbalance between bone formations relative to bone resorption is responsible in bone remodeling. Several studies have suggested that macrolactin A (MA) has potent anti-inflammatory, anti-cancer and anti-angiogenic effects in various cell types. We investigate whether macrolactin A (MA) could inhibit bone loss and enhance bone formation. We used bone marrow monocytes/macrophages (BMMs) cells to study osteoclast activity and MC3T3-E1 cells to study osteoblast activity. MA suppressed tartrate resistant acid phosphatase (TRAP) positive multinucleated cells in a concentration-dependent manner, as well as at a specific time point. MA markedly reduced bone resorption activity and F-actin ring formation. Moreover, MA markedly suppressed receptor activator of nuclear factor k-B ligand (RANKL)-induced osteoclastogenic marker genes and transcription factors in-vitro. MA repressed osteoclast differentiation via activation of the phosphoinositide kinase-3/Akt, extracellular signal-regulated kinase 1/2 (ERK 1/2), c-Jun N-terminal kinase (JNK), nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and c-Fos signaling pathways. MA enhanced pre-osteoblast cell differentiation on mineralization activity, alkaline phosphatase (ALP) activity, and the expression of osteoblastogenic markers including osterix, RUNX-2, SMAD4, BMP-2, and ALP. Importantly, MA repressed lipopolysaccharide (LPS)-induced inflammatory bone loss in mice as shown by TRAP staining of femurs and μCT analysis. Therefore, MA could be a promising candidate for the inhibition and management of osteoporosis, arthritis, and bone lytic diseases.
骨吸收和骨形成之间的失衡会导致几种骨病，如类风湿性关节炎、骨质疏松症和佩吉特病。骨形成相对于骨吸收的失衡是骨重建的原因。几项研究表明，大环内酯 A（MA）在各种细胞类型中具有强大的抗炎、抗癌和抗血管生成作用。我们研究了大环内酯 A（MA）是否可以抑制骨丢失并增强骨形成。我们使用骨髓单核细胞/巨噬细胞（BMM）细胞研究破骨细胞活性，使用 MC3T3-E1 细胞研究成骨细胞活性。MA 呈浓度依赖性以及在特定时间点抑制抗酒石酸酸性磷酸酶（TRAP）阳性多核细胞。MA 显著降低了破骨细胞的骨吸收活性和 F-肌动蛋白环形成。此外，MA 还显著抑制了体外核因子 k-B 配体（RANKL）诱导的破骨细胞生成标记基因和转录因子。MA 通过激活磷酯酰肌醇激酶-3/Akt、细胞外信号调节激酶 1/2（ERK 1/2）、c-Jun N 末端激酶（JNK）、活化 T 细胞核因子，细胞质 1（NFATc1）和 c-Fos 信号通路抑制破骨细胞分化。MA 通过促进前成骨细胞的分化来增强矿化活性、碱性磷酸酶（ALP）活性以及成骨细胞标记物的表达，包括osterix、RUNX-2、SMAD4、BMP-2 和 ALP。重要的是，MA 抑制了脂多糖（LPS）诱导的小鼠炎症性骨丢失，如股骨 TRAP 染色和 μCT 分析所示。因此，MA 可能是抑制和治疗骨质疏松症、关节炎和溶骨性骨疾病的有前途的候选药物。
