Inhibition of STAT1 accelerates bone fracture healing

Abstract

Skeletal fracture healing involves a variety of cellular and molecular events; however, the mechanisms behind these processes are not fully understood. In the current study, we investigated the potential involvement of the signal transducer and activator of transcription 1 (STAT1), a critical regulator for both osteoclastogenesis and osteoblast differentiation, in skeletal fracture healing. We used a fracture model and a cortical defect model in mice, and found that fracture callus remodeling and membranous ossification are highly accelerated in STAT1-deficient mice. Additionally, we found that STAT1 suppresses Osterix transcript levels and Osterix promoter activity in vitro, indicating the suppression of Osterix transcription as one of the mechanisms behind the inhibitory effect of STAT1 on osteoblast differentiation. Furthermore, we found that fludarabine, a potent STAT1 inhibitor, significantly increases bone formation in a heterotopic ossification model. These results reveal previously unknown functions of STAT1 in skeletal homeostasis and may have important clinical implications for the treatment of skeletal bone fracture. ß

Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

“…This may be particularly relevant when STAT3 is hyperactivated as in inflammation-or cancer-induced bone loss. This is supported by an earlier report that STAT1 inhibition promoted bone formation in fracture healing (78), the greater periosteal circumference we observed in Stat1 Ϫ/Ϫ mice, and high alkaline phosphatase activity in cultured osteoblasts with constitutive STAT3 activation (16).…”

Ascorbic acid regulates osterix expression in osteoblasts by activation of prolyl hydroxylase and ubiquitination-mediated proteosomal degradation pathway

“…Furthermore, osterix could be repressed by p53 in reporter assays. Stat1 and E4BP4 have also been identified as negative regulators of osterix expression (46,49). PHDs also regulate the stability of IKK, therefore affecting NF-B pathway (65).…”

Harnessing and Modulating Inflammation in Strategies for Bone Regeneration

“…Absence of IFNg signaling, due to absence of either STAT1 or the IFN-g receptor, increases the number of osteoclasts in bone in vivo, but also increases bone mass. 98,99 Absence of STAT1 also accelerates in vivo fracture healing and subsequent bone remodeling. 99 Gelatin scaffolds loaded with fludarabine, a STAT1 inhibitor, stimulated in vivo ectopic bone formation when implanted subcutaneously in a mouse model.…”

“…98,99 Absence of STAT1 also accelerates in vivo fracture healing and subsequent bone remodeling. 99 Gelatin scaffolds loaded with fludarabine, a STAT1 inhibitor, stimulated in vivo ectopic bone formation when implanted subcutaneously in a mouse model. Dual delivery of BMP-2 and fludarabine revealed an additive effect of the two agents on in vivo ectopic bone formation.…”

“…Dual delivery of BMP-2 and fludarabine revealed an additive effect of the two agents on in vivo ectopic bone formation. 99 Stromal cell-derived factor-1. SDF-1 is a new target in bone regeneration strategies.…”