Previous studies have shown that BM
Previous studies have shown that BM-MSCs can be labeled by markers including Prx1, Dermo1, leptin receptor, and Nestin (Mendelson and Frenette, 2014; Morrison and Scadden, 2014). Our lineage-tracing experiments confirm that Prx1+ BM-MSCs can differentiate into osteoblasts, chondrocytes, and adipocytes in vivo. Moreover, deletion of p38α MAPK in Prx1+ ret inhibitor affects bone mass, growth plates, and bone marrow fat, as well as osteoclastogenesis and bone resorption. However, deletion of p38α in Dermo1+ cells, like deletion of p38α in osteoblasts, only affects BM-MSC osteogenic differentiation and bone formation. These results suggest that Prx1 may be a much early marker than Dermo1 and that Dermo1+ cells may represent a BM-MSC population with limited chondrogenic activity.
In summary, the present study shows that BM-MSC-expressed p38α may take two routes to maintain bone mass and prevent the development of osteoporosis. In particular, p38α is required for proper BM-MSC osteogenic commitment, via the TAK1-NFκB pathway, to maintain proper bone formation, and for OPG synthesis by BM-MSCs to constrain osteoclastogenesis and bone resorption. Moreover, estrogen appears to go through the p38-OPG pathway to preserve the bone. Cytokines or growth factors that can activate p38 MAPKs, e.g., TGFβ1, BMPs, TNFα, and IL6 (Cuadrado and Nebreda, 2010; Han and Sun, 2007; Sorrentino et al., 2008; Yamashita et al., 2008), may regulate bone remodeling via p38α as well.
Introduction Osteoporosis is the most common metabolic bone disease, and it affects many people such as the elderly, long-term bed-ridden patients, astronauts, and persons living sedentary lifestyles (Armbrecht et al., 2011; Edwards et al., 2015; Lau and Guo, 2011; Rachner et al., 2011). Disuse or unloading-induced osteoporosis leads to an insufficient number of osteoblasts or a reduction in their function. These effects are well known as some of the main causes in the pathogenesis of osteoporosis (Kondo et al., 2011; Nakamura et al., 2013). Therefore, drugs that induce the differentiation and proliferation of osteoblasts, thus promoting bone formation, may represent a strategy for the prevention and treatment of osteoporosis, which, however, still remains an unmet medical need. Recent reports showed that glucagon-like peptide-1 (GLP-1), a gastrointestinal hormone whose release is stimulated by ingestion, acts as an important modulator of bone growth and remodeling (Kim et al., 2013; Yamada et al., 2008). In addition, our previous investigation suggested that exendin-4 (Ex-4), a peptide analog of GLP-1, induced bone formation by osteoblast activation in old ovariectomized (OVX) rats (Ma et al., 2013), raising a new question regarding the downstream molecular mechanisms underlying the osteogenic effect. The elucidation of this effect would provide insight into the pathophysiology of osteoporosis and the pharmacological properties of GLP-1 and its analogs. GLP-1 and its analogs exert their physiological and pharmacological effects mainly via the GLP-1 receptor (GLP-1R). However, at present GLP-1R expression in osteoblasts has not been clearly confirmed. Many studies reported that GLP-1R was not expressed in primary osteoblasts and Saos-2 cells (Aoyama et al., 2014; Bollag et al., 2000; Yamada et al., 2008). Other research reported that GLP-1R was expressed in young osteoblasts derived from TE-85 and MG-63, but not in mature osteoblasts derived from Saos-2 osteosarcoma cell line (Pacheco-Pantoja et al., 2011). At the same time, GLP-1R was also detected during osteogenic differentiation of human adipose-derived stem cells (Jeon et al., 2014). In our previous work, we found that Ex-4 osteogenic action in OVX rats was a consequence of the differentiation of bone marrow stromal cells (BMSCs) through the promotion of osteogenesis and a simultaneous suppression of adipogenesis (Ma et al., 2013). Moreover, additional experimental analyses demonstrate the presence of the GLP-1R mRNA and protein in human BMSCs (Sanz et al., 2010). These lines of evidence provide a strong hint that BMSCs might be a cell target that mediates the osteogenic effect of GLP-1 and its analogs.