Gene expression profiling in disease reveals the underlying gene activity changes contributing to the disease and enables targets for therapeutic intervention to be identified. In this study, we investigated gene expression profile in human MSCs from patients of osteoporosis and controls, and then identified biologically active small molecules capable to reverse gene changes of osteoporosis using computational bioinformatics methods. Results show that a total of 5581 genes were differentially expressed between osteoporosis and controls. In addition, we identified large amount of small molecules which can provide new ideas for the therapeutic studies in osteoporosis.
Up to 5581 genes were identified differentially expressed between osteoporosis and control in our approach. These DEGs may play critical roles in the initiation of osteoporosis, and investigation of them may shed new lights on understanding of the molecular mechanism of osteoporosis. Pathway enrichment analysis of these DEGs indicated a total of 9 pathways were dysregulated in the development of osteoporosis, including focal adhesion and MAPK signaling pathway.
Focal adhesions, which are specialized sites of attachment between cells and the extracellular matrix, play a role in cell motility, cell proliferation, signal transduction and have been proposed to function as mechanosensors [24–26]. Osteoporosis is a result of an imbalance of bone formation and resorption. In osteoporosis, the regenerative capacity of bone is compromised, which may involve altered osteoblast activity. This could be attributed to an inappropriate synthesis and assembly of an extracellular matrix (ECM), altered cell adhesion to the ECM, or be due to inappropriate downstream activation of adhesion-mediated signaling cascades through proteins such as focal adhesion kinase (FAK). Perinpanayagam et al. suggested that early adhesion-mediated events, such as cell adhesion, attachment, and FAK signaling may be altered in osteoporotic osteoblast cells . In our result, focal adhesion was the most significant dysfunctional pathways in the initiation of osteoporosis.
MAPK signaling pathways transduces a large variety of external signals, leading to a wide range of cellular responses, including growth, differentiation, inflammation and apoptosis . Several studies have suggested that MAPK signaling pathways contribute greatly to osteoblast differentiation and bone formation via TGF-β and bone morphogenic protein (BMP) signaling pathways. Lee et al. demonstrated that MAPK pathways converge at the Runx2 gene to control mesenchymal precursor cell differentiation following TGF-β induction . Recent study revealed that TGF-β signaling promotes osteoprogenitor proliferation, early differentiation, and commitment to the osteoblastic lineage through the selective MAPKs pathways . In addition, MAPK dependent phosphorylation, TGF-β/BMP signaling, and Runx2 subnuclear targeting converge to induce the osteogenic phenotype .
The identification of a group of small molecules with potential therapeutic efficacy for osteoporosis is an important observation of our work. Data in Table 2 shows that sanguinarine (enrichment score = −0.968) was associated with highly significant negative score, suggesting that this small molecule is capable of targeting osteoporosis. Sanguinarine, a component of sanguinaria extract, has been shown to display antitumor and anti-inflammatory properties in animals [32, 33] and to inhibit neutrophil function . Madan et al. demonstrate that sanguinarine is a potent suppressor of NF-kB activation that blocks the phosphorylation and degradation of IkBα . Recently, it was discovered that the RANK/RANKL/OPG system is an important signal transduction pathway that regulates osteoclast formation . Targeting of this pathway is a novel therapeutic approach in the management of osteoporosis. Therefore, sanguinarine may provide promising targets for the future development of novel treatments of osteoporosis. However, further evaluation for their potential use in the treatment of osteoporosis is still needed.