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Abstract The ability of the extracellular matrix (ECM) to instruct progenitor cell differentiation has generated excitement for the development of materials‐based regenerative solutions. Described a nanoparticulate mineralized collagen glycosaminoglycan (MC‐GAG) material capable of inducing in vivo skull regeneration without exogenous growth factors or ex vivo progenitor cell‐priming is described previously. Here, the contribution of titrating stiffness to osteogenicity is evaluated by comparing noncrosslinked (NX‐MC) and crosslinked (MC) forms of MC‐GAG. While both materials are osteogenic, MC demonstrates an increased expression of osteogenic markers and mineralization compared to NX‐MC. Both materials are capable of autogenously activating the canonical BMPR signaling pathway with phosphorylation of Smad1/5. However, unlike NX‐MC, human mesenchymal stem cells cultured on MC demonstrate significant elevations in the major mechanotransduction mediators YAP and TAZ expression, coincident with β‐catenin activation in the canonical Wnt signaling pathway. Inhibition of YAP/TAZ activation reduces osteogenic expression, mineralization, and β‐catenin activation in MC, with less of an effect on NX‐MC. YAP/TAZ inhibition also results in a reciprocal increase in Smad1/5 phosphorylation and BMP2 expression. The results indicate that increasing MC‐GAG stiffness induces osteogenic differentiation via the mechanotransduction mediators YAP/TAZ and the canonical Wnt signaling pathway, whereas the canonical BMPR signaling pathway is activated independent of stiffness.
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Abstract The instructive capabilities of extracellular matrix components in progenitor cell differentiation have recently generated significant interest in the development of bioinspired materials for regenerative applications. Previously, a correlation was described between the osteogenic capabilities of nanoparticulate mineralized collagen glycosaminoglycan scaffolds (MC‐GAG) and an autogenous activation of small mothers against decapentaplegic ( Smad1/5) in the canonical bone morphogenetic protein receptor (BMPR) pathway with a diminished extracellular signal regulated kinase 1/2 (ERK1/2) activation when compared to nonmineralized collagen glycosaminoglycan scaffolds (Col‐GAG). This work utilizes a canonical BMPR inhibitor (dorsomorphin homologue 1, DMH1) and an inhibitor of the mitogen activated protein kinase/ERK kinase (MEK)/(ERK) cascade (PD98059) to characterize the necessity of each pathway for osteogenesis. While DMH1 inhibits runt‐related transcription factor 2 (Runx2) and bone sialoprotein II (BSPII) gene expression of primary human mesenchymal stem cells (hMSCs) on MC‐GAG, PD98059 inhibits BSPII expression on Col‐GAG independent of Runx2 expression. DMH1 inhibits mineralization on both Col‐GAG and MC‐GAG, however, PD98059 only inhibits mineralization on Col‐GAG. DMH1 inhibits both Smad1/5 phosphorylation and Runx2 protein expression, whereas PD98059 inhibits ERK1/2 and c‐Jun amino‐terminal kinase 1/2 (JNK1/2) phosphorylation without affecting Runx2. Thus, activation of the canonical BMPR signaling is necessary for osteogenic differentiation and mineralization of hMSCs on Col‐GAG or MC‐GAG. The MEK/ERK cascade, intimately tied to JNK activation, is necessary for Runx2‐independent osteogenesis on Col‐GAG, while completely dispensable in osteogenesis on MC‐GAG.