TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation

Transforming growth factor-beta（TGF-β）/bone morphogenetic protein（BMP） plays a fundamental role in the regulation of bone organogenesis through the activation of receptor serine/threonine kinases. Perturbations of TGF-β/BMP activity are almost invariably linked to a wide variety of clinical outcomes, i.e., skeletal, extra skeletal anomalies, autoimmune, cancer, and cardiovascular diseases. Phosphorylation of TGF-β（I/II） or BMP receptors activates intracellular downstream Smads, the transducer of TGF-β/BMP signals. This signaling is modulated by various factors and pathways, including transcription factor Runx2. The signaling network in skeletal development and bone formation is overwhelmingly complex and highly time and space specific.Additive, positive, negative, or synergistic effects are observed when TGF-β/BMP interacts with the pathways of MAPK, Wnt, Hedgehog（Hh）, Notch, Akt/m TOR, and mi RNA to regulate the effects of BMP-induced signaling in bone dynamics. Accumulating evidence indicates that Runx2 is the key integrator, whereas Hh is a possible modulator, mi RNAs are regulators, and b-catenin is a mediator/regulator within the extensive intracellular network. This review focuses on the activation of BMP signaling and interaction with other regulatory components and pathways highlighting the molecular mechanisms regarding TGF-β/BMP function and regulation that could allow understanding the complexity of bone tissue dynamics.

Human iPSC-derived iMSCs improve bone regeneration in mini-pigs

Autologous bone marrow concentrate(BMC)and mesenchymal stem cells(MSCs)have beneficial effects on the healing of bone defects.To address the shortcomings associated with the use of primary MSCs,induced pluripotent stem cell(iPSC)-derived MSCs(iMSCs)have been proposed as an alternative.The aim of this study was to investigate the bone regeneration potential of human iMSCs combined with calcium phosphate granules(CPG)in critical-size defects in the proximal tibias of mini-pigs in the early phase of bone healing compared to that of a previously reported autograft treatment and treatment with a composite made of either a combination of autologous BMC and CPG or CPG alone.iMSCs were derived from iPSCs originating from human fetal foreskin fibroblasts(HFFs).They were able to differentiate into osteoblasts in vitro,express a plethora of bone morphogenic proteins(BMPs)and secrete paracrine signaling-associated cytokines such as PDGF-AA and osteopontin.Radiologically and histomorphometrically,HFF-iMSC+CPG transplantation resulted in significantly better osseous consolidation than the transplantation of CPG alone and produced no significantly different outcomes compared to the transplantation of autologous BMC+CPG after 6 weeks.The results of this translational study imply that iMSCs represent a valuable future treatment option for load-bearing bone defects in humans.