Abstract
Bone constantly remodels between resorption by osteoclasts and formation by osteoblasts; therefore the functions of osteoblasts are pivotal for maintaining homeostasis of bone mass. Transient receptor potential vanilloid 4 (TRPV4), a type of mechanosensitive channel, has been reported to be a key regulator in bone remodeling. However, the relationship between TRPV4 and osteoblast function remains largely elusive. Only little is known about the spatial distribution change of TRPV4 during osteoblastic differentiation and related signal events. Based on three-dimensional super-resolution microscopy, our results clearly showed a different distribution of TRPV4 in undifferentiated and differentiated osteoblasts, which reflected the plasma membrane translocation of TRPV4 along with prolonged differentiation. GSK1016790A (GSK101), the most potent agonist of TRPV4, triggered rapid calcium entry and calmodulin-dependent protein kinase II (CaMKII) phosphorylation via TRPV4 activation in a differentiation-dependent manner, indicating that the abundance of TRPV4 at the cell surface resulting from differentiation may be related to the modulation of Ca2+ response and CaMKII activity. These data provide compelling evidences for the plasma membrane translocation of TRPV4 during osteoblastic differentiation as well as demonstrate the regulation of downstream Ca2+/CaMKII signaling.
Highlights
Bone is a dynamic tissue that undergoes continuous remodeling between formation of new bone matrix by osteoblasts and resorption of preexisting bone matrix by osteoclasts (Crockett et al 2011)
We detected the expressions of Transient receptor potential vanilloid 4 (TRPV4) in the isolated rat calvarial osteoblasts at different stages of differentiation
The levels of TRPV4 mRNA were increased in parallel to the increase in differentiation, which corroborated previous findings (Suzuki et al 2013), which somehow declined on day 7
Summary
Bone is a dynamic tissue that undergoes continuous remodeling between formation of new bone matrix by osteoblasts and resorption of preexisting bone matrix by osteoclasts (Crockett et al 2011). A proper balance between osteoblasts and osteoclasts is vital for maintaining bone construction and function Attenuation of osteoblast formation may lead to bone loss, osteoporosis, and eventually debilitating fractures (Zaidi 2007). Osteoblasts originate from mesenchymal progenitors that, with the appropriate stimulation, differentiate into preosteoblasts and to mature, functional osteoblasts (Kassem et al 2008). Mature osteoblasts express many biochemical markers and transcription factors (Gundberg 2000; Marie 2008). By undergoing extracellular matrix maturation and mineralization, osteoblasts form bone-like mineralized nodules in vivo and in vitro (Blair et al 2017). An increase in proliferation results in a greater number of bone-forming cells, whereas increased differentiation enhances the capability
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