• Humans
• beta Catenin/metabolism
• Cell Differentiation
• Cell Proliferation
• Cells, Cultured
• Interleukin-17/metabolism
• Ligamentum Flavum/metabolism
• Ossification, Heterotopic
• Osteogenesis

• Differentiation
• Immunomodulatory
• Mesenchymal stromal cell
• Paracrine signalling
• Secretome
• Substrate stiffness

• Tissue Inhibitor of Metalloproteinase-2/pharmacology
• Interleukin-6
• Cell Differentiation
• Tissue Engineering
• Mesenchymal Stem Cell Transplantation
• Culture Media, Conditioned/pharmacology

• immunogenetics
• rheumatic diseases

• Humans
• Extracellular Vesicles/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Mesenchymal Stem Cells/metabolism
• Axial Spondyloarthritis
• Biology

• axial spondyloarthritis
• biological agents
• cytokines
• innate immunity
• personalized medicine

• Humans
• Spondylarthritis
• Immunity, Innate
• HLA-B27 Antigen/genetics
• Lymphocytes
• Axial Spondyloarthritis

• National Key Research and Development Program of China
• National Natural Science Foundation of China

Bone regeneration is a tightly regulated process that ensures proper repair and functionality after injury. The delicate balance between bone formation and resorption is governed by cytokines and signaling molecules released during the inflammatory response. Interleukin (IL)-17A, produced in the early phase of inflammation, influences the fate of osteoprogenitors. Due to their inherent capacity to differentiate into osteoblasts, mesenchymal stem/stromal cells (MSCs) contribute to bone healing and regeneration. This review presents an overview of IL-17A signaling and the leading cellular and molecular mechanisms by which it regulates the osteogenic differentiation of MSCs. The main findings demonstrating IL-17A’s influence on osteoblastogenesis are described. To this end, divergent information exists about the capacity of IL-17A to regulate MSCs’ osteogenic fate, depending on the tissue context and target cell type, along with contradictory findings in the same cell types. Therefore, we summarize the data showing both the pro-osteogenic and anti-osteogenic roles of IL-17, which may help in the understanding of IL-17A function in bone repair and regeneration.

• Interleukin-17
• Mesenchymal stem cells
• Osteoblast
• Bone
• Osteogenesis
• Inflammation

Ankylosing spondylitis (AS), characterized by inflammatory lesions and osteophyte formation, is a common immune rheumatic disease affecting the sacroiliac and axial joints. A high-intensity mechanical load is known to accelerate the heterotopic ossification associated with enthesitis in AS. Thus, the present study explored whether decreased mechanical load could delay the heterotopic ossification in AS. First, 24-week-old female BALB/c mice were induced with proteoglycan (PG) to establish an AS model. The AS-induced pathological and bone morphological changes of the sacroiliac joint were confirmed by hematoxylin and eosin staining and microCT analysis, respectively. Subsequently, the mice were treated with interventions of different mechanical loads. Using reverse transcription-quantitative PCR, it was revealed that expression levels of the osteogenesis-related genes bone morphogenetic protein-2, runt-related transcription factor 2 and osteocalcin were significantly reduced in sacroiliac bone tissue after intervention with a reduced mechanical load. The level of mechanosensory microRNA (miR)-103 increased in response to reduced mechanical loads. Consistently, in groups with reduced mechanical load, proteins with mechanical functions, including ρ-associated coiled-coil-containing protein kinase 1 (ROCK1), phosphorylated (p)-Erk1/2 and β-catenin, were reduced compared with the PG control. A dual-luciferase assay verified that miR-103 binds to the 3'-untranslated region end of Rock1 mRNA, thus negatively regulating the activity of Rock1 and affecting pathological ossification during AS. However, immunohistochemical staining indicated that the expression of dickkopf Wnt signaling pathway inhibitor 1, an inhibitor of the Wnt/β-catenin pathway, was increased in sacroiliac tissues. The results indicated that tail suspension decreased the mechanical load, thus reducing the bone formation in AS mice. Furthermore, tail suspension could inhibit the activation of mechanical kinase ROCK1 and p-Erk1/2 in the MAPK signaling pathway by upregulating miR-103, thereby inhibiting the classical osteogenesis-related Wnt/β-catenin pathway in AS. In summary, the present study uncovered the ameliorative effect of suspension on AS and its therapeutic potential for AS.

• Wnt/β-catenin signaling pathway
• ankylosing spondylitis
• heterotopic ossification
• mechanical load
• microRNA-103

• B cell
• T cell
• ankylosing spondylitis
• osteoimmunology
• skeletal system

• Ankylosing spondylitis
• Interleukin-17
• Interleukin-1β
• Mesenchymal stem cells
• Neutrophil extracellular traps

To explore the role of microRNA (miR-21) in new bone formation in ankylosing spondylitis (AS) as mediated by different concentration of tumor necrosis factor-α (TNF-α).

Fibroblasts isolated from the hips of patients with AS were induced to osteogenesis. These cells were then stimulated with varying concentrations of TNF-α. MicroRNA-21 expressions were evaluated using reverse transcription–polymerase chain reaction (RT-PCR) and osteogenesis was detected via Alizarin Red S (ARS) staining and measurement of alkaline phosphatase (ALP) activity. Relative expressions of p-STAT3, Nuclear STAT3, cytoplasm STAT3, Runx2, BMP2, osteopontin, osteocalcin, and LC3B in AS fibroblasts were measured after exposure to different concentrations of TNF-α. The STAT3-inhibiting small interfering RNA allowed further exploration on its impact on miR-21 and primary miR-21 expressions. A proteoglycan-induced arthritis (PGIA) Balb/c mouse model was established in order to monitor sacroiliac joint (SIJ) inflammation and subsequent damage through magnetic resonance image. Serum miR-21 and TNF-α expressions were evaluated using RT-PCR and enzyme-linked immunosorbent assay. At week 16, mice models were transfected intravenously with miR-21 overexpressing agomir and miR-21 inhibiting antagomir for 7 successive days. The rate of abnormal bone formation at SIJ was evaluated using microcomputed tomography and hematoxylin and eosin staining at week 24. Western blot analysis enabled quantification of STAT-3, JAK-2, and interleukin (IL)-17A expressions present in the SIJ.

The in vitro miR-21 expression and osteogenesis activity were noted to be augmented in the setting of low TNF-α concentrations (0.01-0.1 ng/mL) while they were depressed in settings with higher TNF-α concentrations (1-10 ng/mL). Samples with the most distinct ARS manifestation and ALP activity as well as the highest miR-21 expressions were those who received 0.1 ng/mL of TNF-α. Primary miR-21 was found to be notable raised by Si-STAT3, while the converse effect was seen in mature miR-21 expressions. Intravenous injection of exogenous miR-21 contributed to new bone formation and significantly elevated expressions of STAT3, JAK2, and IL-17 in PGIA mice.

The results revealed that miR-21 may act as a potential mediator between new bone formation and inflammation in AS.

• JAK/STAT-3 signaling
• TNF-α
• ankylosing spondylitis
• miR-21