title: Biomechanical forces exert anabolic effects on osteoblasts by activation of SMAD 1/5/8 through type 1 BMP receptor.
abstract: Osteoblasts are mechanosensitive cells, which respond to biomechanical stimuli to regulate the bone structure through anabolic and catabolic gene regulation. To examine the effects of mechanical forces on the osteogenic responses through the SMAD signaling in osteoblasts, the cells were cultured in well-characterized mechanoresponsive 3-D scaffolds and exposed to 10% dynamic compressive strain (Cmp) at 1 Hz. Subsequently, SMAD phosphorylation and osteogenic gene induction was examined. Osteoblasts cultured in 3-D scaffolds exhibited increased constitutive SMAD 1/5/8 phosphorylation, as compared to monolayers cultures. This SMAD 1/5/8 phosphorylation was further upregulated after 10, 30 and 60 min in response to Cmp, exhibiting a peak activation at 30 min. No significant changes in SMAD2 phosphorylation were observed, suggesting signals generated by Cmp may not activate the Transforming Growth Factor-β signaling cascade. Subsequently, biomechanical stimulation-induced SMAD 1/5/8 phosphorylation upregulated the expression of osteogenic genes such as Osteoprotegrin, Msx2 and Runx2. Dorsomorphin, a selective inhibitor of the bone morphogenetic protein (BMP) receptor type 1 (BMPR1), blocked Cmp-induced SMAD 1/5/8 phosphorylation, as well as Osteoprotegrin, Msx2 and Runx2 gene expression. Collectively, the present findings demonstrate that biomechanical stimulation of osteoblasts activates SMAD 1/5/8 in the BMP signaling pathway through BMPR1 and may enhance osteogenesis by upregulating SMAD-dependent osteogenic genes.
authors.affiliation: Department of Orthopaedic Surgery, University of Regensburg, Bad Abbach, Germany. brath27@gmail.com
authors.forename: B
authors.initials: B
authors.lastname: Rath
authors.forename: J
authors.initials: J
authors.lastname: Nam
authors.forename: J
authors.initials: J
authors.lastname: Deschner
authors.forename: J
authors.initials: J
authors.lastname: Schaumburger
authors.forename: M
authors.initials: M
authors.lastname: Tingart
authors.forename: S
authors.initials: S
authors.lastname: Grässel
authors.forename: J
authors.initials: J
authors.lastname: Grifka
authors.forename: S
authors.initials: S
authors.lastname: Agarwal
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D055595:Mechanical Phenomena; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism*; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D013314:Stress, Mechanical; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D011720:Pyrazoles; D011743:Pyrimidines; D051896:Smad Proteins, Receptor-Regulated; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; C516138:dorsomorphin; D052005:Bone Morphogenetic Protein Receptors, Type I