TRPV4 calcium influx controls sclerostin protein loss independent of purinergic calcium oscillations

Williams, Katrina; Leser, Jenna; Gould, Nicole R.; Joca, Humberto C.; Lyons, James S.; Khairallah, Ramzi J.; Ward, Christopher W.; Stains, Joseph P.

doi:10.1016/j.bone.2020.115356

Cited by 25 publications

(22 citation statements)

References 45 publications

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“…To characterize the dynamics of mechanically stimulated sclerostin protein loss in osteocytes, we examined two sclerostin expressing cell lines, Ocy454 osteocytes and UMR106 osteosarcoma cells. Consistent with our previous work (15,16), we observed the mechano-activated increase in CaMKII phosphorylation and decrease in sclerostin protein abundance in both Ocy454 osteocytes ( Fig. 1B) and UMR106 osteosarcoma cells (Fig.…”

Section: Sclerostin Protein Is Rapidly Lost After Mechanical Load Insupporting

confidence: 92%

“…This rapid regulation strongly suggested post-translational control of sclerostin abundance. Consistent with the possibility of post-translational control of sclerostin, we recently reported that a single 5-minute bout of FSS, as used here, does not decrease Sost mRNA levels despite a decrease in sclerostin protein (16). To confirm the post-translational control of sclerostin, Ocy454 cells were transfected with either a myc-or GFP-tagged sclerostin expression vector under control of a CMV promoter, which is not regulated by the same transcriptional elements that regulate Sost transcription.…”

Section: Sclerostin Protein Is Rapidly Lost After Mechanical Load Insupporting

confidence: 90%

“…Using a recently established osteocyte-like cell line Ocy454 cells, which is one of the few cell lines that reliably express detectable sclerostin protein (13,14), we described a mechanotransduction pathway that regulates osteocyte sclerostin protein abundance in response to FSS in vitro (Fig. 1A) (15,16). Using this in vitro model, we previously found that osteocyte mechanosignaling required a subset of detyrosinated microtubules, which transduce load signals to activate NADPH Oxidase 2 (NOX2), which produces reactive oxygen species (ROS) signals that elicit a Transient Receptor Potential Vanilloid 4 (TRPV4)-dependent primary calcium (Ca 2+ ) influx.…”

Section: Introductionmentioning

confidence: 99%

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Disparate Bone Anabolic Cues Activate Bone Formation by Regulating the Rapid Lysosomal Degradation of Sclerostin Protein

Gould

Williams

Joca

et al. 2020

Preprint

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The down regulation of sclerostin mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation that occurs hours after stimulation. Here, we describe, for the first time, the rapid post-translational degradation of sclerostin protein by the lysosome following mechanical load or PTH. We present a unifying model, integrating both new and established mechanically- and hormonally-activated effectors into the regulated degradation of sclerostin by lysosomes. Using an in vivo mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using Gaucher disease iPSCs. These results inform a paradigm shift in how bone anabolic cues post-translationally regulate sclerostin and expands our understanding of how osteocytes regulate this fundamentally important protein to regulate bone formation.

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Section: Sclerostin Protein Is Rapidly Lost After Mechanical Load Insupporting

confidence: 92%

Section: Sclerostin Protein Is Rapidly Lost After Mechanical Load Insupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Disparate Bone Anabolic Cues Activate Bone Formation by Regulating the Rapid Lysosomal Degradation of Sclerostin Protein

Gould

Williams

Joca

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…This rapid regulation strongly suggested post-translational control of sclerostin abundance. Consistent with the possibility of post-translational control of sclerostin, we recently reported that a single 5-minute bout of FSS, as used here, does not decrease Sost mRNA levels despite a decrease in sclerostin protein (19). To confirm the post-translational control of sclerostin, Ocy454 cells were transfected with either a myc-or GFP-tagged sclerostin expression vector under control of a CMV promoter, which is not controlled by the same transcriptional elements that regulate Sost transcription.…”

Section: Sclerostin Protein Is Rapidly Lost After Mechanical Load Insupporting

confidence: 90%

“…Our prior work showed sclerostin protein disappearance on a minutes time scale following FSS in Ocy454 cells, an effect that required activation of CaMKII (Figure 1A) (18,19). To more precisely characterize the dynamics of mechanically stimulated sclerostin protein loss in osteocytes, we examined two sclerostin expressing cell lines, Ocy454 osteocytes and UMR106 osteosarcoma cells.…”

Section: Sclerostin Protein Is Rapidly Lost After Mechanical Load Inmentioning

confidence: 96%

Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

Gould

Williams

Joca

et al. 2021

eLife

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The down regulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the Sost gene hours after stimulation. Using mouse models and rodent cell lines, we describe the rapid, minutes-scale post-translational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically- and hormonally-activated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation by preventing sclerostin degradation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation.

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TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc

Easson,

Savadipour,

Gonzalez

et al. 2023

JOR Spine

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BackgroundThe ion channel transient receptor potential vanilloid 4 (TRPV4) critically transduces mechanical forces in the IVD, and its inhibition can prevent IVD degeneration due to static overloading. However, it remains unknown whether different modes of loading signals through TRPV4 to regulate the expression of inflammatory cytokines. We hypothesized that TRPV4 signaling is essential during static and dynamic loading to mediate homeostasis and mechanotransduction.MethodsMouse functional spine units were isolated and either cyclically compressed for 5 days (1 Hz, 1 h, 10% strain) or statically compressed (24 h, 0.2 MPa). Conditioned media were monitored at 6 h, 24 h, 2 days, and 5 days, with and without TRPV4 inhibition. Effects of TRPV4 activation was also evaluated without loading. The media was analyzed for a panel of 44 cytokines using a microbead array and then a correlative network was constructed to explore the regulatory relationships during loading and TRPV4 inhibition. After the loading regimen, the IVDs were evaluated histologically for degeneration.ResultsActivation of TRPV4 led to an increase interleukin‐6 (IL‐6) family of cytokines (IL‐6, IL‐11, IL‐16, and leukemia inhibitory factor [LIF]) and decreased the T‐cell (CCL3, CCL4, CCL17, CCL20, CCL22, and CXCL10) and monocyte (CCL2 and CCL12) recruiting chemokines by the IVD. Dynamic and static loading each provoked unique chemokine correlation networks. The inhibition of TRPV4 during dynamic loading dysregulated the relationship between LIF and other cytokines, while the inhibition of TRPV4 during static loading disrupted the connectivity of IL‐16 and VEGFA.ConclusionsWe demonstrated that TRPV4 critically mediates the cytokine production following dynamic and static loading. The activation of TRPV4 upregulated a diverse set of cytokines that may suppress the chemotaxis of T‐cells and monocytes, implicating the role of TRPV4 in maintaining the immune privilege of healthy IVD.

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TRPV4 calcium influx controls sclerostin protein loss independent of purinergic calcium oscillations

Cited by 25 publications

References 45 publications

Disparate Bone Anabolic Cues Activate Bone Formation by Regulating the Rapid Lysosomal Degradation of Sclerostin Protein

Disparate Bone Anabolic Cues Activate Bone Formation by Regulating the Rapid Lysosomal Degradation of Sclerostin Protein

Disparate bone anabolic cues activate bone formation by regulating the rapid lysosomal degradation of sclerostin protein

TRPV4 differentially controls inflammatory cytokine networks during static and dynamic compression of the intervertebral disc

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