The Role Of β-adrenergic Receptors In Osteogenesis And Adipogenesis Of Mouse Mesenchymal Stem Cells

It has been established that the sympathetic nervous system (SNS) innervates bone remodeling and fat metabolism viaβ-adrenergic receptors (β-ARs). The role of SNS in bone remodeling has been focused on bone growth, bone resorption and bone mass aspects. The importance of SNS signaling in fat metabolism has been predominantly demonstrated in lipolysis and thermogenesis aspects. Since osteoblasts and adipocytes are major MSC-derived cell types, and abnormal osteogenesis and adipogenesis may be a causation of osteoporosis and obesity in aged people, it is essential to fully understand the mechanisms involved in MSC osteogenesis and adipogenesis. Whether SNS is involved in MSC osteogenesis or adipogenesis, however, is still unclear. In the present study, we used mouse bone marrow derived MSCs to study the effects ofβ-AR signaling on osteogenesis and adipogenesis. The expression profiles ofβ-ARs on mouse MSCs during differentiation were analyzed and the effect of someβ-AR ligands on MSC osteogenesis and adipogenesis was evaluated. Furthermore, the potential involvement of the cAMP/PKA pathway was also investigated.The result showed that: (1) Both the mRNA and the protein expression levels ofβ2- andβ3-AR were up-regulated following MSC osteogenesis and adipogenesis. (2)β-AR agonists negatively while antagonists positively affect MSC osteogenesis, respectively. The inhibitory effect of theβ-AR agonist (ISO) could be reversed by either PH, ICI or SR, respectively the generalβ-antagonist, the specificβ2- andβ3-antagonist. The reversal potency could be ranked as PH > ICI > SR, which suggested that bothβ2- andβ3-AR are involved in MSC osteogenesis, with theβ2-subtype being dominant. (3) Also,β-AR agonists negatively while antagonists positively affect MSC adipogenesis. The inhibitory effect of ISO could be restored by either PH, ICI, or SR, and the reversal capability was ranked as PH > SR > ICI. These data indicated that bothβ2- andβ3-AR are involved in MSC adipogenesis, withβ3-AR being the dominant subtype. (4) In both osteogenic and adipogenic MSCs, the cAMP concentrations could be modulated byβ-agonists and/or antagonists, and the effect of ISO could be abolished by the protein kinase A (PKA) inhibitor H89, which demonstrated thatβ-adrenergic signals regulate MSC osteogenesis and adipogenesis via the cAMP/PKA signaling.Taken together, data in the current study indicated thatβ-ARs are expressed on MSCs,β2-AR andβ3-AR are major functional receptors in MSC osteogenesis and adipogenesis, respectively.β-AR agonists negatively while antagonists positively affect MSC osteogenesis and adipogenesis. The effect ofβ-ARs on MSC osteogenesis and adipogenesis is partially mediated via the cAMP/PKA pathway. On one hand, this study will contribute to a greater understanding on the cellular mechanisms responsible for MSC osteogenesis and adipogenesis. On the other hand, it will provide some insight into the prevention and treatment of some bone related diseases and obesity.