Macrolactin A protects against LPS-induced bone loss by regulation of bone remodeling

• Published in: European journal of pharmacology 2020-09, Vol.883, p.173305-173305, Article 173305
• Main Authors: Sapkota, Mahesh, Gao, Ming, Li, Liang, Yang, Ming, Shrestha, Saroj Kumar, Choi, Hyukjae, Soh, Yunjo
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Bone Density Conservation Agents - pharmacology; Bone loss; Bone Remodeling - drug effects; Cell Differentiation - drug effects; Disease Models, Animal; Gene Expression Regulation; Lipopolysaccharides; LPS; Macrolactin A; Macrolides - pharmacology; Male; Mice; Mice, Inbred ICR; Osteoblast; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoblasts - pathology; Osteoclast; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; Osteogenesis - drug effects; Osteoporosis; Osteoporosis - chemically induced; Osteoporosis - metabolism; Osteoporosis - pathology; Osteoporosis - prevention & control; Signal Transduction
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173305

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. [Display omitted]