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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/106428
Cooperation of calcium, BMP and WNT signalling for optimal osteoblast differentiation. Application for bone tissue engineering
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[eng] At least two specific features differentiate bone from other tissues, a blend of organic and mineral components, and a cellular organization with a hierarchical commitment degree. During bone remodeling osteoclasts dissolve the mineral and degrade the organic bone components, releasing the degradation products to the extracellular space. Bone is one of the hardest connective tissues in the human body. However, skeletal tissue can be injured by trauma, atrophied by tooth loss, destroyed by pathological conditions or incompletely formed during congenital craniofacial bone defects, such as cleft palate. Autogenous bone is considered the “gold standard” to regenerate bone defects. However, wherever bone is harvested undesirable and detrimental effects are produced at the donor area. To avoid these drawbacks, bone tissue engineering has emerged to provide an alternative to autogenous bone harvesting drawbacks. It has been shown by several “in vitro” an “in vivo” studies that BMP-2 promotes osteogenic differentiation and bone formation. High doses are required (e.g. 1-45 mg/ml in animal models) to obtain acceptable outcomes. However, several side effects, such as inflammation and ectopic bone formation, have been reported after using elevated amounts of BMP-2. In this work we employed a composite Gelatin/CaSO4 scaffold that allows for an early expansion of seeded MSC´s, which is followed by an increased level of osteogenic differentiation after 10 days in culture. Furthermore, this seeded scaffold enhanced bone formation in a mouse model of critical-size calvarial defects. More importantly, ex vivo pretreatment of MSC´s with low amounts of BMP-2 (2nM) and Wnt3a (50 ng/ml) for 24 hours cooperatively increases the expression of osteogenic markers in vitro and bone regeneration in the critical-size calvarial defect in the mouse model. Moreover, we determined the molecular mechanisms involved in cooperation between Ca2+ and BMP-2 in MSC´s at early and late differentiating points. Early, at 24 hours, we observed an intracellular network activation which is antagonistic to BMP-2/Smad signalling. More importantly, a significant cooperative effect between Ca2+ and BMP-2 is observed after 10 days. Ca2+ promotes an autocrine/paracrine feed-forward loop that reinforces the BMP-2 osteogenic input. Of note, Ca2+ alone induced similar osteogenic effects as BMP-2 alone in long-term cell culture. In conclusion, cytokine signalling (such as BMP-2) and signalling from the mineral component (such as Ca2+) signals interact during bone remodeling. Early on, Ca2+ inhibits BMP-2 differentiation effect but later amplifies and reinforces the osteogenic BMP-2 effect.
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AQUINO MARTÍNEZ, Rubén francisco. Cooperation of calcium, BMP and WNT signalling for optimal osteoblast differentiation. Application for bone tissue engineering. [consulta: 15 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/106428]