Estrogen depletion on In vivo osteocyte calcium signaling responses to mechanical loading

Lewis, Karl J.; Cabahug‐Zuckerman, Pamela; Boorman-Padgett, James; Basta‐Pljakic, Jelena; Louie, Joyce; Stephen, Samuel J.; Spray, David C.; Thi, Mia M.; Seref‐Ferlengez, Zeynep; Majeska, Robert J.; Weinbaum, Sheldon; Schaffler, Mitchell B.

doi:10.1016/j.bone.2021.116072

Cited by 20 publications

(11 citation statements)

References 81 publications

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“…Our systematic review has identified six studies in which all of them reported an increase of intracellular calcium release by hMSCs after FSS application. This is supported by recent studies, which show direct evidence of FSS effects on bone cell activity, i.e., increased calcium signaling in osteocytes directly resulting from FSS (Lewis et al, 2017;Lewis et al, 2021).…”

Section: Genes or Metabolites Reported By At Least Three Studiessupporting

confidence: 79%

Fluid flow shear stress and tissue remodeling—an orthodontic perspective: evidence synthesis and differential gene expression network analysis

Nile,

Folwaczny,

Wichelhaus

et al. 2023

Front. Bioeng. Biotechnol.

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Introduction: This study aimed to identify and analyze in vitro studies investigating the biological effect of fluid-flow shear stress (FSS) on cells found in the periodontal ligament and bone tissue.Method: We followed the PRISMA guideline for systematic reviews. A PubMed search strategy was developed, studies were selected according to predefined eligibility criteria, and the risk of bias was assessed. Relevant data related to cell source, applied FSS, and locus-specific expression were extracted. Based on this evidence synthesis and, as an original part of this work, analysis of differential gene expression using over-representation and network-analysis was performed. Five relevant publicly available gene expression datasets were analyzed using gene set enrichment analysis (GSEA).Result: A total of 6,974 articles were identified. Titles and abstracts were screened, and 218 articles were selected for full-text assessment. Finally, 120 articles were included in this study. Sample size determination and statistical analysis related to methodological quality and the ethical statement item in reporting quality were most frequently identified as high risk of bias. The analyzed studies mostly used custom-made fluid-flow apparatuses (61.7%). FSS was most frequently applied for 0.5 h, 1 h, or 2 h, whereas FSS magnitudes ranged from 6 to 20 dyn/cm2 depending on cell type and flow profile. Fluid-flow frequencies of 1 Hz in human cells and 1 and 5 Hz in mouse cells were mostly applied. FSS upregulated genes/metabolites responsible for tissue formation (AKT1, alkaline phosphatase, BGLAP, BMP2, Ca2+, COL1A1, CTNNB1, GJA1, MAPK1/MAPK3, PDPN, RUNX2, SPP1, TNFRSF11B, VEGFA, WNT3A) and inflammation (nitric oxide, PGE-2, PGI-2, PTGS1, PTGS2). Protein-protein interaction networks were constructed and analyzed using over-representation analysis and GSEA to identify shared signaling pathways.Conclusion: To our knowledge, this is the first review giving a comprehensive overview and discussion of methodological technical details regarding fluid flow application in 2D cell culture in vitro experimental conditions. Therefore, it is not only providing valuable information about cellular molecular events and their quantitative and qualitative analysis, but also confirming the reproducibility of previously published results.

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Section: Genes or Metabolites Reported By At Least Three Studiessupporting

confidence: 79%

Fluid flow shear stress and tissue remodeling—an orthodontic perspective: evidence synthesis and differential gene expression network analysis

Nile,

Folwaczny,

Wichelhaus

et al. 2023

Front. Bioeng. Biotechnol.

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“…Osteocytes regulate bone homeostasis in response to mechanical loading via a range of mechanosensing mechanisms, [ 40 , 41 , 42 ] including integrin attachments, [ 43 , 44 , 45 ] their glycocalyx, [ 46 , 47 ] and the primary cilium. [ 48 , 49 ] Thus, changes in osteocyte behavior induced by TGF‐β from cancer cells may disturb bone biology, with disruptions to osteocyte regulation of bone remodeling linked to age‐related degeneration [ 50 ] osteoporosis, [ 51 , 52 , 53 ] osteoarthritis [ 54 ] and osteogenesis imperfecta. [ 55 ] In particular, it is well‐established that primary cilia are key to normal osteocyte function, mechanoresponsiveness and regulation of other bone cell types, [ 56 ] and thus the cancer cell‐induced changes in osteocyte cilia we observed will likely also affect bone biology, such as the disruption of mechanosensitivity observed here.…”

Section: Discussionmentioning

confidence: 99%

A Novel Primary Cilium‐Mediated Mechanism Through which Osteocytes Regulate Metastatic Behavior of Both Breast and Prostate Cancer Cells

Verbruggen,

Nolan,

Duffy

et al. 2023

Advanced Science

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Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly understood. Using a series of co‐culture, conditioned media, human cancer spheroid, and organ‐on‐a‐chip experiments, this study reveals that osteocytes suppress cancer cell proliferation and increase migration via tumor necrosis factor alpha (TNF‐α) secretion. This action is regulated by osteocyte primary cilia and associated intraflagellar transport protein 88 (IFT88). Furthermore, it shows that cancer cells block this mechanism by secreting transforming growth factor beta (TGF‐β), which disrupts osteocyte cilia and IFT88 gene expression. This bi‐directional crosstalk signaling between osteocytes and cancer cells is common to both breast and prostate cancer. This study also proposes that osteocyte inhibition of cancer cell proliferation decreases as cancer cells increase, producing more TGF‐β. Hence, a positive feedback loop develops accelerating metastatic tumor growth. These findings demonstrate the importance of cancer cell‐osteocyte signaling in regulating breast and prostate bone metastases and support the development of therapies targeting this pathway.

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“…In females also, the osteocyte has been excluded as the main mediator of sex steroid effects on skeletal adaptation (39). Recent studies nevertheless suggest that estrogen withdrawal results in intrinsic changes in the ability of the osteocyte to sense and respond to mechanical loading (40,41). Of note, Cre recombinase activity in abovementioned conditional knockouts was driven by the Dmp1 or osteocalcin promoter, resulting in sex steroid receptor ablation in mature osteoblasts and/or terminally differentiated osteocytes.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of AR or ERα in Extrahypothalamic Neurons Does not Affect Osteogenic Response to Loading in Male Mice

et al. 2022

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Failure of bone mass maintenance in spite of functional loading is an important contributor to osteoporosis and related fractures. While the link between sex steroids and the osteogenic response to loading is well-established, the underlying mechanisms are unknown, hampering clinical relevance. Androgens inhibit mechanoresponsiveness in male mice, but the cell type mediating this effect remains unidentified. To evaluate the role of neuronal sex steroid receptor signaling in the male bone’s adaptive capacity, we subjected adult male mice with an extrahypothalamic neuron-specific knockout of the androgen receptor (N-ARKO) or the estrogen receptor alpha (N-ERαKO) to in vivo mechanical stimulation of the tibia. Loading increased cortical thickness in the control animals mainly through periosteal expansion, as total cross-sectional tissue area and cortical bone area but not medullary area were higher in the loaded compared to the unloaded tibia. Trabecular bone volume fraction also increased upon loading in the control group, mostly due to trabecular thickening. N-ARKO and N-ERαKO males displayed a loading response at both the cortical and trabecular bone compartments which was not different from their control littermates. In conclusion, we show that the presence of AR or ERα in extrahypothalamic neurons is dispensable for the osteogenic response to mechanical loading in male mice.

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Estrogen depletion on In vivo osteocyte calcium signaling responses to mechanical loading

Cited by 20 publications

References 81 publications

Fluid flow shear stress and tissue remodeling—an orthodontic perspective: evidence synthesis and differential gene expression network analysis

Fluid flow shear stress and tissue remodeling—an orthodontic perspective: evidence synthesis and differential gene expression network analysis

A Novel Primary Cilium‐Mediated Mechanism Through which Osteocytes Regulate Metastatic Behavior of Both Breast and Prostate Cancer Cells

Inactivation of AR or ERα in Extrahypothalamic Neurons Does not Affect Osteogenic Response to Loading in Male Mice

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