SOCS1, the feedback regulator of STAT1/3, inhibits the osteogenic differentiation of rat bone marrow mesenchymal stem cells

Our study showed that Signal transducer and activator of transcription (STAT)1 and STAT3 phosphorylation was firstly upregulated in the early stage of osteogenic differentiation (OD), and quickly eliminated in hours. Following with phosphorylation of STAT1/3, its downstream feedback regulator Suppressor of cytokine signaling 1 (SOCS1) protein also underwent a quick elevation. Further activation and deactivation of STAT1/3, by administrated with Colivelin and Nifuroxazide in Bone mesenchymal stem cells (BMSCs), increased and decreased SOCS1 expression, inhibited and promoted OD of BMSCs, respectively, as evidenced by Alizarin staining, alkaline phosphatase (ALP) activity, and determination of Run-related transcription factor 2 (RUNX2), Osteocalcin (OCN), ALP, and Bone sialoprotein (BSP). In addition, administration of Colivelin and Nifuroxazide caused and blocked inflammation and apoptosis of BMSCs. To further elucidate the role of STAT1/3-SOCS1 regulatory loop on OD of BMSCs, we overexpressed or silenced SOCS1 in BMSCs during OD. WB data showed that overexpression of SOCS1 repressed STAT1/3 phosphorylation, and knockdown of SOCS1 increased the phosphorylated STAT1/3. Further mechanism study showed that OD of BMSCs was elevated or reduced by SOCS1 overexpression or knockdown, respectively. The findings presenting indicated that the STAT1/3-SOCS1 axis may be exploited as an innovative strategy to enhance osteogenesis in regenerative medicine.

Automated summary

Our study revealed that phosphorylation of STAT1 and STAT3 is initially upregulated in the early stage of osteogenic differentiation (OD), but quickly eliminated within hours. This phosphorylation is followed by an increase in the downstream feedback regulator SOCS1 protein. By modulating the activation and deactivation of STAT1/3, as well as administering Colivelin and Nifuroxazide in Bone mesenchymal stem cells (BMSCs), we were able to increase and decrease the expression of SOCS1, leading to inhibition and promotion of BMSCs' OD, respectively. Additionally, Colivelin and Nifuroxazide treatment caused inflammation and apoptosis of BMSCs. Further experiments involving the overexpression or knockdown of SOCS1 during OD revealed that overexpression repressed STAT1/3 phosphorylation, while knockdown increased the phosphorylation. Mechanistically, OD of BMSCs was enhanced or reduced by SOCS1 overexpression or knockdown, respectively. These findings suggest that the STAT1/3-SOCS1 axis could be targeted as an innovative strategy to enhance osteogenesis in regenerative medicine.