Regulation of intracellular Ca2+/CaMKII signaling by TRPV4 membrane translocation during osteoblastic differentiation

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 Ca 2? 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 Ca 2? /CaMKII signaling.

TRPV4 Activator-Containing CMT-Hy Hydrogel Enhances Bone Tissue Regeneration In Vivo by Enhancing Mitochondrial Health

“…32,48 Mature osteoblasts have a higher TRPV4 expression as compared to immature osteoblasts, suggesting that TRPV4 expression increases during the osteoblast differentiation. 49,50 Mutations in TRPV4 are known to induce different channelopathies, where neuromuscular and/or skeletal dysplasia are common. 51 All of these indicate TRPV4 as an important molecular target for efficient bone healing.…”

“…Bone repair needs tight regulation of Ca 2+ signaling and high metabolic states (i.e., mitochondrial homeostasis) of osteoblasts. − Migration, proliferation, and differentiation of osteogenic cells are decisive for tissue repair, wherein an increase in the oxidative metabolism (mitochondrial bioenergetics) is necessary to awaken dormant cells and speed up this healing process. Reports suggest the importance of TRPV4 in maintaining Ca 2+ homeostasis within cells and within the mitochondria. , Mature osteoblasts have a higher TRPV4 expression as compared to immature osteoblasts, suggesting that TRPV4 expression increases during the osteoblast differentiation. , Mutations in TRPV4 are known to induce different channelopathies, where neuromuscular and/or skeletal dysplasia are common . All of these indicate TRPV4 as an important molecular target for efficient bone healing.…”

“…This is relevant as the expression of TRPV4 is stiffness-dependent . Activation of TRPV4 increases the intracellular Ca 2+ ion, which is essential for bone homeostasis. , In osteoblasts, Ca 2+ acts as a crucial second messenger and controls numerous cell signaling events including the CamKII pathway, where TRPV4 may play a role. , Adhesion of MSCs or osteoblasts to the implant surface is a critical step required for osteointegration . In this context, TRPV4 is known to be present in the focal adhesion points and TRPV4–actin interaction might also be relevant for this .…”

TRPV4 regulates osteoblast differentiation and mitochondrial function that are relevant for channelopathy

“…The above-mentioned observations open up possibilities for utilizing TRPV4 (including other TRP channels) as potential molecular target/s for bone-loss condition such as osteoporosis ( McNulty et al, 2015 ). Recently, it has been reported that during RCO differentiation, the expression and distribution of TRPV4 increases in the plasma membrane while decreases in the cytosol ( Hu et al, 2019 ). Our data further suggests that 4αPDD-mediated mineralization could be attenuated by RN1734, suggesting that TRPV4 activation-mediated functions were partly reversed by its inhibition.…”

Hydrogel cultures reveal Transient Receptor Potential Vanilloid 4 regulation of myofibroblast activation and proliferation in valvular interstitial cells

“…47 TRPV4 is known to be able to directly activate CaM. 48 Whether or not the TRPV4-CaM pathway plays a direct role in VIC proliferation remains to be studied further. Here, we have shown that proliferation itself is dependent on microenvironment stiffness and suggest that mechanosensors other than TRPV4 are likely regulating proliferation.…”