STAT3 promotes bone fracture healing by enhancing the FOXP3 expression and the suppressive function of regulatory T cells

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a key signaling protein in the skeletal system as well as in the immune system. Accumulating evidence demonstrates that the inflammatory response is deeply involved in the healing process of bone fractures, but how the immune system is regulated during this process is unclear. In this study, we examined STAT3-mediated regulation of immunity in adult patients with closed tibia fracture. In all patients, the expression and activation of STAT3 peaked at around day 7 to day 14 after surgery, and gradually decreased during the rest of the healing period. At day 7 (peak STAT3 expression and phosphorylation), the CD4 CD25 T cells from bone fracture patients presented the highest level of STAT3 activation among lymphocyte subsets. Therefore, we investigated the role of STAT3 in CD4 CD25 T cells. The level of FOXP3 expression by CD4 CD25 T cells was directly correlated with the level of STAT3 phosphorylation in these cells. The level of STAT3 phosphorylation in CD4 CD25 T cells was also inversely correlated with the level of IFN-γ and TNF-α secretion in peripheral blood mononuclear cells. Inhibition of STAT3 significantly suppressed FOXP3 and IL-10 expression by CD4 CD25 T cells, as well as the ability of CD4 CD25 T cells to suppress T-cell IFN-γ and TNF-α secretion. Furthermore, early healers patients presented significantly higher STAT3 expression and phosphorylation than late healers, possibly due to the higher IL-6 and IL-10 levels in the serum of early healing patients. Together, these data demonstrated that STAT3 was beneficial to bone fracture healing, possibly by enhancing Treg-mediated suppression of counteracting inflammations, and suggested that STAT3 could be used as a prognostic marker to identify otherwise undistinguishable patients at risk of developing delayed union or nonunion.

Excreted‐secreted antigens of Toxoplasma gondii inhibit Foxp3 via IL‐2Rγ/JAK3/Stats pathway

“…35 Additionally, Foxp3 expression induced by IL-2 is positively regulated via Stat5 and Stat3. Sun et al 36 revealed that Stat3promoted bone fracture healing is due to the enhancement in Foxp3 expression and inhibitory function of Tregs. We found that ESA administration markedly inhibited Foxp3 via the downregulation of P-Stat3 and P-Stat5, whereas forced expression of Stat3 and Stat5 partially reversed the ESA-mediated Foxp3 downregulation (Figures 2 and 3).…”

CoCl2, a mimic of hypoxia, enhances bone marrow mesenchymal stem cells migration and osteogenic differentiation via STAT3 signaling pathway

“…Hypoxia regulates osteogenic cells proliferation and angiogenesis through extracellular regulated protein kinases (ERK)‐1/2 and protein kinase B (AKT) pathway (Nicolaidou et al, ; Guo et al, ). STAT3 pathway is closely connected to cell migration and bone cells differentiation and activity (Reed et al, ; Sun et al, ). Our previous study demonstrated that the STAT3 pathway enhances pre‐osteoclasts migration (Li et al, ).…”

The Adenosine A2A Receptor Agonist Accelerates Bone Healing and Adjusts Treg/Th17 Cell Balance through Interleukin 6

“…T lymphocytes are important cells involved in adaptive immunity [42][43][44]. Animal studies have found that the loss of T lymphocytes or a significant reduction in the number of T lymphocytes can affect the maturation of osteoblasts and lead to slow bone mineralization [42][43][44][45]. Fracture repair and bone remodeling have been shown to be slow in rats with T lymphocyte deficiency [42][43][44][45].…”

“…Animal studies have found that the loss of T lymphocytes or a significant reduction in the number of T lymphocytes can affect the maturation of osteoblasts and lead to slow bone mineralization [42][43][44][45]. Fracture repair and bone remodeling have been shown to be slow in rats with T lymphocyte deficiency [42][43][44][45]. Bone marrow transplantation can reverse the slow healing of fracture in animals with low T lymphocyte immunity [44,45].…”

“…Fracture repair and bone remodeling have been shown to be slow in rats with T lymphocyte deficiency [42][43][44][45]. Bone marrow transplantation can reverse the slow healing of fracture in animals with low T lymphocyte immunity [44,45]. Clinically, it was also found that the bone fragility of HIV patients increased and the rate of osteoporosis was significantly higher than that of normal people [46].…”