Angelicin Alleviates Post-Trauma Osteoarthritis Progression by Regulating Macrophage Polarization via STAT3 Signaling Pathway.

Post-trauma osteoarthritis (PTOA) is the most common articular disease characterized by degeneration and destruction of articular cartilage (Bultink and Lems, Curr. Rheumatol Rep., 2013, 15, 328). Inflammatory response of local joint tissue induced by trauma is the most critical factor accelerating osteoarthritis (OA) progression (Sharma et al., 2019; Osteoarthritis. Cartilage, 28, 658-668). M1/M2 macrophages polarization and repolarization participates in local inflammation, which plays a major role in the progression of OA (Zhang et al., 2018; Ann. Rheum. Dis., 77, 1524-1534). The regulating effect of macrophage polarization has been reported as a potential therapy to alleviate OA progression. Synovitis induced by polarized macrophages could profoundly affect the chondrocyte and cartilage matrix (Zhang et al., 2018; Ann. Rheum. Dis., 77, 1524-1534). Generally, anti-inflammatory medications widely used in clinical practice have serious side effects. Therefore, we focus on exploring a new therapeutic strategy with fewer side effects to alleviate the synovitis. Angelicin (ANG) is traditional medicine used in various folk medicine. Previous studies have revealed that angelicin has an inhibitory effect on inflammation (Wei et al., 2016; Inflammation, 39, 1876-1882), tumor growth (Li et al., 2016; Oncology reports, 36, 3,504-3,512; Wang et al., 2017; Molecular Medicine Reports, 16, 5441-5449), DNA damage (Li et al., 2019; Exp. Ther. Med., 18, 1899-1906), and virus proliferation (Li et al., 2018; Front. Cell. Infect. Microbiol., 8, 178). But its specific effects on influencing the process of OA were rarely reported. In this study, the molecular mechanism of angelicin in vivo and in vitro was clearly investigated. Results showed that angelicin could regulate the M1/M2 ratio and function and alleviate the development of PTOA in the meanwhile. Bone marrow monocytes were isolated and induced by macrophage colony-stimulating factor (M-CSF), lipopolysaccharide (LPS) and interferon (IFN)-γ for M1 polarization and interleukin (IL)-4/IL-13 for M2 polarization. Subsequently, repolarization intervention was performed. The results indicate that angelicin can repolarize M1 toward M2 macrophages by upregulating the expression of CD9. Besides, angelicin can also protect and maintain M2 polarization in the presence of LPS/IFN-γ, and subsequently downregulate the expression of inflammatory mediators such as IL-1ß and TNF-α. Mechanistically, angelicin can activate the p-STAT3/STAT3 pathway by conducting CD9/gp130 to repolarize toward M2 macrophages. These results suggest angelicin can alleviate the progression of OA by regulating M1/M2 polarization via the STAT3/p-STAT3 pathway. Therefore, angelicin may have a promising application and potential therapeutic value in OA clinical treatment.

Tumour dormancy in inflammatory microenvironment: A promising therapeutic strategy for cancer-related bone metastasis.

Cancer metastasis is a unique feature of malignant tumours. Even bone can become a common colonization site due to the tendency of solid tumours, including breast cancer (BCa) and prostate cancer (PCa), to metastasize to bone. Currently, a previous concept in tumour metabolism called tumour dormancy may be a promising target for antitumour treatment. When disseminated tumour cells (DTCs) metastasize to the bone microenvironment, they form a flexible regulatory network called the "bone-tumour-inflammation network". In this network, bone turnover as well as metabolism, tumour progression, angiogenesis and inflammatory responses are highly unified and coordinated, and a slight shift in this balance can result in the disruption of the microenvironment, uncontrolled inflammatory responses and excessive tumour growth. The purpose of this review is to highlight the regulatory effect of the "bone-tumour-inflammation network" in tumour dormancy. Osteoblast-secreted factors, bone turnover and macrophages are emphasized and occupy in the main part of the review. In addition, the prospective clinical application of tumour dormancy is also discussed, which shows the direction of future research.

Epothilone B prevents lipopolysaccharide-induced inflammatory osteolysis through suppressing osteoclastogenesis via STAT3 signaling pathway.

Inflammatory osteolysis is a common osteolytic specificity that occurs during infectious orthopaedic surgery and is characterized by an imbalance in bone homeostasis due to excessive osteoclast bone resorption activity. Epothilone B (Epo B) induced α-tubulin polymerization and enhanced microtubule stability, which also played an essential role in anti-inflammatory effect on the regulation of many diseases. However, its effects on skeletal system have rarely been investigated. Our study demonstrated that Epo B inhibited osteoclastogenesis in vitro and prevented inflammatory osteolysis in vivo. Further analysis showed that Epo B also markedly induced mature osteoclasts apoptosis during osteoclastogenesis. Mechanistically, Epo B directly suppressed osteoclastogenesis by the inhibitory regulation of the phosphorylation and activation of PI3K/Akt/STAT3 signaling directly, and the suppressive regulation of the CD9/gp130/STAT3 signaling pathway indirectly. The negative regulatory effect on STAT3 signaling further restrained the translocation of NF-κB p65 and NFATc1 from the cytosol to the nuclei during RANKL stimulation. Additionally, the expression of osteoclast specific genes was also significantly attenuated during osteoclast fusion and differentiation. Taken together, these findings illustrated that Epo B protected against LPS-induced bone destruction through inhibiting osteoclastogenesis via regulating the STAT3 dependent signaling pathway.

P2X7 receptor acts as an efficient drug target in regulating bone metabolism system.

Skeletal system is a highly dynamic system going through continuous resorption and reconstruction to maintain homeostasis, which is influenced by numerous factors. Once the balance is disrupted, various kinds of bone diseases may occur such as osteoporosis. It has been well known that ATP (adenosine triphosphate), an important signaling molecule, is important in maintaining the dynamic balance of bone matrix. ATP mainly functions through P2X receptors, a kind of ATP receptors expressed by various kinds of bone cells to regulate the whole network of skeleton system. Among P2X receptors, P2X7 plays a crucial role in bone since P2X7 is widely expressed by bone cells and the mutation of P2X7 receptor is associated with kinds of bone diseases. It's acknowledged that P2X7 acts as a potential therapeutic target for clinical treatment of bone-related diseases but further investigations are needed for the practical application. However, since P2X7 has a complicated effect in many aspects, the exact role of P2X7 in skeleton system is ambiguous. This review discusses the function of P2X7 in bone and other cells and their general effect on skeleton system, especially focusing on the possible clinical application for bone diseases.