Bone marrow-derived mesenchymal stem cells promote healing of rabbit tibial fractures via JAK-STAT signaling pathway

Abstract

Influence of bone marrow-derived mesenchymal stem cells (BMMSCs) on the healing of rabbit tibial fractures and the role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway in fracture healing were explored. Rabbit BMMSCs were isolated and cultured in vitro, and their purity was determined using flow cytometry. Rabbit fracture models were established, and injected with BMMSCs, BMMSCs + TG101348 or TG101348, with those injected with an equal volume of normal saline as control group, and the repair of fracture ends was evaluated via X-ray examination 3 weeks later. The BMMSCs isolated in vitro grew well, and flow cytometry assay results showed that the positive expression rates of cluster of differentiation (CD)90 and CD105 in cells were 99.21 and 99.56%, respectively, with no CD45 expressed. According to the results of CCK-8 assay, TG101348 lowered the proliferation level of BMMSCs, and the wound healing assay revealed that the migration ability of BMMSCs at 24 and 48 h was substantially weaker than that in control group (P<0.05). After induction of osteogenic differentiation for 3 weeks, alizarin red staining results manifested that osteogenic induction group had notably more calcium nodules than TG101348 group (P<0.05). Compared with those in control group, the protein expression levels of p-JAK2 and p-STAT3 were remarkably raised by osteogenic induction (P<0.05), but the protein expression levels of JAK2, p-JAK2 and p-STAT3 were considerably decreased by TG101348 (P<0.05). It was found through the X-ray examination that the rabbits in control group and those injected with BMMSCs recovered well, and the latter had larger external calluses at fracture ends than the former, while the fracture ends of those injected with TG101348 and BMMSCs + TG101348 were not healed completely. BMMSCs promote healing of rabbit tibial fractures through the JAK-STAT signaling pathway.

JAK2 Inhibition by Fedratinib Reduces Osteoblast Differentiation and Mineralisation of Human Mesenchymal Stem Cells

“…We observed that Fedratinib treatment reduced osteoblastic differentiation, in vitro mineralisation, and the expression of osteoblast-related genes. The role of the JAK/STAT signalling pathway in triggering osteoblastic differentiation has been widely described [ 1 , 2 , 3 , 5 , 15 , 23 , 31 , 32 ].…”

“…Osteoblastic differentiation, bone development, mineralisation, and fracture repair can be mediated by several intracellular signalling pathways, such as the JAK/STAT pathway [ 23 , 31 ]. The in vitro activation of the JAK/STAT signalling can promote ALP activity, and increase OC expression, suggesting a vital role for JAK/STAT in osteoblastic differentiation [ 23 ]. Moreover, the fracture-healing capacity was impaired in JAK2-deficient mice.…”

“…Moreover, the fracture-healing capacity was impaired in JAK2-deficient mice. A plausible explanation for this observation is that inhibiting the expression of JAK2 leads to decoupling from STAT3, consequently inhibiting the osteoblastic differentiation of hBMSCs [ 23 , 33 ]. In addition, the inhibition of JAK2 after the in vitro osteogenic differentiation of hBMSCs inhibited the production of osteoblasts, demonstrating the importance of JAK2/STAT3 signalling in the osteoblastic differentiation of hBMSCs [ 23 ].…”

“…JAK/STAT signalling plays an important role in bone development. It has been shown that inhibition of JAK2 disconnects it from the downstream mediator STAT3, leading to the inhibition of hMSCs differentiation into osteoblasts [ 8 , 23 ].…”

The Histone Demethylase KDM3B Promotes Osteo-/Odontogenic Differentiation, Cell Proliferation, and Migration Potential of Stem Cells from the Apical Papilla

“…Then, the Path-net analysis results suggest that the Janus kinase signal transducer and activator of transcription (JAK-STAT) and Toll-like receptor signaling pathways may be involved in the functional regulation of KDM3B. At present, some researches have shown that the JAK-STAT pathway can modulate cell migration potentials of BMSCs [ 40 ] while regulating bone regeneration and promoting angiogenesis [ 41 – 43 ]. Among them, the STAT1-CCND1/CDK6 axis promotes proliferation by accelerating the transition from the G0/G1 phase to the S phase [ 44 , 45 ].…”