Abstract
Side-effects associated to the use of bone morphogenetic proteins into scaffold-based devices for bone repair highlight the necessity for identifying new therapeutic targets that potentially improve bone healing in adults. In this sense, we recently demonstrated the age-associated decrease in the mechanosensitivity of bone marrow mesenchymal stromal/stem cells (MSCs) and identified c-Jun N-terminal kinase 3 (JNK3) as a mechanically-activated modulator of the superior osteogenic potential of MSCs derived from children (C-MSCs) in comparison to adults (A-MSCs). Building on this work, the aim of this study was to design a JNK3-activated collagen-nanohydroxyapatite (coll-nHA) scaffold that restore the child bone healing capacity in adults. Results revealed that JNK3 activator (JNK3*) enhanced A-MSC’ alkaline phosphatase (ALP) activity to the same extent of C-MSCs by facilitating the activation of JNK3. Moreover, A-MSCs cultured on the coll-JNK3* scaffold (collagen-scaffold containing JNK3*) showed positive uptake of the JNK3*, upregulation of early osteogenic markers as well as increased ALP activity and mineralization. More importantly, rat critical calvarial defects treated with coll-JNK3* for 28 days showed a significantly higher 18.07 % bone volume fraction in comparison to rats treated with Coll-nHA −6.04%- and empty defects −2.58%. Which correlated with the presence of a larger amount of blood vessels and mineralized tissue in samples treated with coll-JNK3* when compared with coll-nHA and empty defects. In conclusion, the coll-JNK3* capacity to enhance osteogenesis and bone healing by activating JNK3 highlights how by understanding the stem cell mechanobiology we can improve the development of next generation therapeutics for tissue repair.
