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Skeletal Mechanobiology
Published in Jiro Nagatomi, Eno Essien Ebong, Mechanobiology Handbook, 2018
Alesha B. Castillo, Christopher R. Jacobs
Once recruited to newly resorbed sites, osteoprogenitors differentiate into mature bone-forming osteoblasts (Figure 13.1c) via activation of several osteogenic signaling pathways. Of these, Wnt signaling is critical at all stages of skeletal maintenance.18 Wnts are secreted glycoproteins that bind a receptor complex comprised of a seven-pass transmembrane protein, frizzled (Fz), and a single pass transmembrane protein of the low-density lipoprotein (LDL) receptor-related protein (LRP) family.19 Canonical Wnt signaling involves several proteins, including dishevelled (Dsh), axin, adenomatous polyposis coli (APC), glycogen synthase kinase (GSK)-3β, and β-catenin. β-catenin is a cytoplasmic phosphoprotein, which, in the absence of Wnt signaling, is targeted for degradation through phosphorylation by GSK-3β. However, upon Wnt binding, Dsh is phosphorylated leading to the phosphorylation and inactivation of GSK-3β, allowing β-catenin to accumulate in the cytoplasm. Subsequently, β-catenin translocates to the nucleus where it interacts with the T-cell and lymphoid enhancer (TCF-LEF) transcription factors to affect gene transcription.19 Target genes include Runx220 and Osterix,21 both of which are osteoblast-specific transcription factors critical in osteoblast differentiation, proliferation, activity, and apoptosis.22 Wnt signaling is inhibited by several proteins including sclerostin, which is encoded by the gene sclerosteosis (SOST),23 dickkopf1 (Dkk1),24 secreted frizzled-related protein 1 (sFRP1),25 and Wise.26 Thus, osteoblast differentiation is regulated by the spatial and temporal expression of Wnt-signaling modulators.
Biochemical and transcriptional analyses of cadmium-induced mitochondrial dysfunction and oxidative stress in human osteoblasts
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Cristina Monteiro, José Miguel P. Ferreira de Oliveira, Francisco Pinho, Verónica Bastos, Helena Oliveira, Francisco Peixoto, Conceição Santos
Our findings demonstrate that Cd increased morphological damage, as evidenced by rise in number of fragmented mitochondria supporting severe dysfunction observed in osteoblast mitochondria and energy processing. It should be noted that some recovery was detected after 48 h for lower Cd concentrations suggesting a reversible process occurred, while at higher Cd concentrations increased the presence of swelling, correlated with the increased apoptosis (Oliveira et al. 2014). The pathways regulating such responses in osteoblasts remain unknown. Arbon et al. (2012) using Saos-2 cells, reported that Cd inhibited osteoblasts proliferation via ERK signaling pathway and identified sclerostin (SOST), whose main function is to inhibit bone formation, as a target for metal-induced osteotoxicity. Ha et al. (2016), using Saos-2 and MG-63 cells found that the calmodulin-dependent phosphodiesterase pathway facilitated Cd-induced sustained ERK activation leading to apoptosis. Messner et al. (2016) noted that Cd-induced death signaling starts with the causation of DNA damage and a cytosolic calcium flux, and that these two events lead to an apoptosis signaling-related mitochondrial membrane depolarization and classical DNA damage response.