Gold nanoparticles exhibit anti-osteoarthritic effects via modulating interaction of the "microbiota-gut-joint" axis.

Osteoarthritis (OA) is a common degenerative joint disease that can cause severe pain, motor dysfunction, and even disability. A growing body of research indicates that gut microbiota and their associated metabolites are key players in maintaining bone health and in the progression of OA. Short-chain fatty acids (SCFAs) are a series of active metabolites that widely participate in bone homeostasis. Gold nanoparticles (GNPs) with outstanding anti-bacterial and anti-inflammatory properties, have been demonstrated to ameliorate excessive bone loss during the progression of osteoporosis (OP) and rheumatoid arthritis (RA). However, the protective effects of GNPs on OA progression are not clear. Here, we observed that GNPs significantly alleviated anterior cruciate ligament transection (ACLT)-induced OA in a gut microbiota-dependent manner. 16S rDNA gene sequencing showed that GNPs changed gut microbial diversity and structure, which manifested as an increase in the abundance of Akkermansia and Lactobacillus. Additionally, GNPs increased levels of SCFAs (such as butyric acid), which could have improved bone destruction by reducing the inflammatory response. Notably, GNPs modulated the dynamic balance of M1/M2 macrophages, and increased the serum levels of anti-inflammatory cytokines such as IL-10. To sum up, our study indicated that GNPs exhibited anti-osteoarthritis effects via modulating the interaction of "microbiota-gut-joint" axis, which might provide promising therapeutic strategies for OA.

Dynamic chromatin accessibility landscapes of osteoblast differentiation and mineralization.

Bone acts as a self-healing organ, which undergoes continuous regeneration process that is tightly regulated by the cooperation of osteoclasts with the capability of bone resorption and osteoblasts with the capability of bone formation. Generally, bone marrow derived mesenchymal stem cells (BMSCs) differentiated to final osteoblasts have been considered as critical role in bone remodeling. In this regard, several transcription factors (TFs) whose binding sites are initially hidden deep within accessible chromatin that participate in modulating osteoblast differentiation and bone matrix mineralization. Then, it is necessary to explore further the dynamic changes about the epigenetic transcription machinery during osteoblastogenesis. Here, we performed the chromatin accessibility and transcriptomic landscape of osteoblast differentiation and mineralization by using transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-Seq). Our data found that global chromatin accessibility during osteoblastogenesis was extensively improved. Above this, it is shown that key target genes including Col6a3, Serpina3n, Ms4a4d, Lyz2, Phf11b and Grin3a were enriched in differential loci RNA-seq and ATAC-Seq peaks with continuous changed tendency during osteoblasts differentiation and mineralization. In addition, Analysis of Motif Enrichment (AME) was used to elucidate TFs which modulated these target genes. In this study, it was shown for the first time that these important TFs including MEF2A, PRRX1, Shox2 and HOXB13 could alter promoter accessibility of target genes during osteoblastogenesis. This helps us understand how TF binding motif accessibility influences osteoblast differentiation. In addition, it also suggests that modulating the chromatin accessibility of osteogenesis could be developed as the promising strategies to regulate bone regeneration.

The crucial mechanism and therapeutic implication of RNA methylation in bone pathophysiology.

Methylation is the most common posttranscriptional modification in cellular RNAs, which has been reported to modulate the alteration of RNA structure for initiating relevant functions such as nuclear translocation and RNA degradation. Recent studies found that RNA methylation especially N6-methyladenosine (m6A) regulates the dynamic balance of bone matrix and forms a complicated network in bone metabolism. The modulation disorder of RNA methylation contributes to several pathological bone diseases including osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), and so on. In the review, we will discuss advanced technologies for detecting RNA methylation, summarize RNA methylation-related biological impacts on regulating bone homeostasis and pathological bone diseases. In addition, we focus on the promising roles of RNA methylation in early diagnosis and therapeutic implications for bone-related diseases. Then, we aim to establish a theoretical basis for further investigation in this meaningful field.

Beyond immunosuppressive effects: dual roles of myeloid-derived suppressor cells in bone-related diseases.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells (IMCs) with immunosuppressive functions, whereas IMCs originally differentiate into granulocytes, macrophages, and dendritic cells (DCs) to participate in innate immunity under steady-state conditions. At present, difficulties remain in identifying MDSCs due to lacking of specific biomarkers. To make identification of MDSCs accurately, it also needs to be determined whether having immunosuppressive functions. MDSCs play crucial roles in anti-tumor, angiogenesis, and metastasis. Meanwhile, MDSCs could make close interaction with osteoclasts, osteoblasts, chondrocytes, and other stromal cells within microenvironment of bone and joint, and thereby contributing to poor prognosis of bone-related diseases such as cancer-related bone metastasis, osteosarcoma (OS), rheumatoid arthritis (RA), osteoarthritis (OA), and orthopedic trauma. In addition, MDSCs have been shown to participate in the procedure of bone repair. In this review, we have summarized the function of MDSCs in cancer-related bone metastasis, the interaction with stromal cells within the bone microenvironment as well as joint microenvironment, and the critical role of MDSCs in bone repair. Besides, the promising value of MDSCs in the treatment for bone-related diseases is also well discussed.