Activation of Focal Adhesion Kinase Restores Simulated Microgravity-Induced Inhibition of Osteoblast Differentiation via Wnt/Β-Catenin Pathway

Fan, Cuihong; Wu, Zhaojia; Cooper, David M.; Magnus, Adam; Harrison, Kim D.; Eames, B. Frank; Chibbar, Rajni; Groot, Gary; Huang, Junqiong; Genth, Harald; Zhang, Jun; Tan, Xing; Deng, Yulin; Xiang, Jim

doi:10.3390/ijms23105593

Cited by 11 publications

(9 citation statements)

References 60 publications

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“…Based on evidence that integrin responses are involved in bone loss associated with microgravity, studies using simulated microgravity indicated that several pathways regulated by integrins, through focal adhesion kinase (FAK), mTORC1, AMPK, and ERK1/2, are affected by low gravity in an osteoblast-like cell line [220]. Microgravity was then shown to downregulate FAK, Wnt/Beta catenin, and signaling downstream of Wnt/beta catenin.…”

Section: Evidence For Integrin-mediated Response To Low Gravitymentioning

confidence: 99%

“…As a consequence, several markers of osteoblast differentiation and bone formation were decreased. In a hind limb unloading model, bone loss was observed, and this was prevented by using an activator of FAK [220]. Although this pathway may contribute to bone loss in low gravity, FAK is crucial for many cell types under many conditions, and unless an FAK-targeting treatment could be focused on osteoblasts, this does not appear to provide a route for preventing bone loss in low gravity.…”

Section: Evidence For Integrin-mediated Response To Low Gravitymentioning

confidence: 99%

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Receptors Implicated in Microgravity-Induced Bone Loss

Martinez,

Pelegrine,

Holliday

2024

Receptors

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For humans to explore and colonize the universe, both engineering and physiological obstacles must be successfully addressed. A major physiological problem is that humans lose bone rapidly in microgravity. Understanding the underlying mechanisms for this bone loss is crucial for designing strategies to ameliorate these effects. Because bone physiology is entangled with other organ systems, and bone loss is a component of human adaptation to microgravity, strategies to reduce bone loss must also account for potential effects on other systems. Here, we consider the receptors involved in normal bone remodeling and how this regulation is altered in low-gravity environments. We examine how single cells, tissues and organs, and humans as a whole are affected by low gravity, and the role of receptors that have been implicated in responses leading to bone loss. These include receptors linking cells to the extracellular matrix and to each other, alterations in the extracellular matrix associated with changes in gravity, and changes in fluid distribution and fluid behavior due to lack of gravity that may have effects on receptor-based signaling shared by bone and other regulatory systems. Inflammatory responses associated with the environment in space, which include microgravity and radiation, can also potentially trigger bone loss.

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Section: Evidence For Integrin-mediated Response To Low Gravitymentioning

confidence: 99%

Section: Evidence For Integrin-mediated Response To Low Gravitymentioning

confidence: 99%

Receptors Implicated in Microgravity-Induced Bone Loss

Martinez,

Pelegrine,

Holliday

2024

Receptors

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“…This was first recorded in the mid-1970s by Skylab astronauts, who experienced a monthly bone mass reduction of 1–2% compared to pre-flight and ground-based controls [ 3 , 4 ]. Subsequent investigations have highlighted the activation of the RANKL/RANK/OPG, PPARγ, and PKA/CREB signaling pathways in microgravity, whereas the Wnt/β-catenin and BMP/Smad pathways are suppressed, leading to enhanced bone resorption and inhibited bone formation [ 5 , 6 , 7 , 8 , 9 ]. (c) Prolonged use of medications like anticonvulsants, glucocorticoids, sedatives, or chemotherapeutic agents [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway

Zhao,

Wang,

et al. 2024

IJMS

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The microgravity conditions in outer space are widely acknowledged to induce significant bone loss. Recent studies have implicated the close relationship between Atp6v1h gene and bone loss. Despite this, the role of Atp6v1h in bone remodeling and its molecular mechanisms in microgravity have not been fully elucidated. To address this, we used a mouse tail suspension model to simulate microgravity. We categorized both wild-type and Atp6v1h knockout (Atp6v1h+/-) mice into two groups: regular feeding and tail-suspension feeding, ensuring uniform feeding conditions across all cohorts. Analysis via micro-CT scanning, hematoxylin-eosin staining, and tartrate-resistant acid phosphatase assays indicated that wild-type mice underwent bone loss under simulated microgravity. Atp6v1h+/- mice exhibited bone loss due to Atp6v1h deficiency but did not present aggravated bone loss under the same simulated microgravity. Transcriptomic sequencing revealed the upregulation of genes, such as Fos, Src, Jun, and various integrin subunits in the context of simulated microgravity and Atp6v1h knockout. Real-time quantitative polymerase chain reaction (RT-qPCR) further validated the modulation of downstream osteoclast-related genes in response to interactions with ATP6V1H overexpression cell lines. Co-immunoprecipitation indicated potential interactions between ATP6V1H and integrin beta 1, beta 3, beta 5, alpha 2b, and alpha 5. Our results indicate that Atp6v1h level influences bone loss in simulated microgravity by modulating the Fos-Jun-Src-Integrin pathway, which, in turn, affects osteoclast activity and bone resorption, with implications for osteoporosis. Therefore, modulating Atp6v1h expression could mitigate bone loss in microgravity conditions. This study elucidates the molecular mechanism of Atp6v1h’s role in osteoporosis and positions it as a potential therapeutic target against environmental bone loss. These findings open new possibilities for the treatment of multifactorial osteoporosis.

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“…Specific facilities, such as the monoaxial clinostats Rotating Wall Vessel (RWV) and Rotary Cell Culture System (RCCS), and the Random Positioning Machine (RPM) can be used to create µg in research laboratories [14][15][16][17]. The majority of research in this field has primarily focused on specific cell types, such as osteoblasts/osteoclasts [18][19][20], myofibers [21], endothelial cells [22][23][24], stem cells [25,26], fibroblasts [27][28][29][30][31] chondrocytes [32], lymphocytes [33] and other immune cells [34], with limited attention given to kidney cells [35,36].…”

Section: Introductionmentioning

confidence: 99%

Modeled microgravity unravels the roles of mechanical forces in renal progenitor cell physiology

Melica,

Cialdai,

La Regina

et al. 2024

Stem Cell Res Ther

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Background The glomerulus is a highly complex system, composed of different interdependent cell types that are subjected to various mechanical stimuli. These stimuli regulate multiple cellular functions, and changes in these functions may contribute to tissue damage and disease progression. To date, our understanding of the mechanobiology of glomerular cells is limited, with most research focused on the adaptive response of podocytes. However, it is crucial to recognize the interdependence between podocytes and parietal epithelial cells, in particular with the progenitor subset, as it plays a critical role in various manifestations of glomerular diseases. This highlights the necessity to implement the analysis of the effects of mechanical stress on renal progenitor cells. Methods Microgravity, modeled by Rotary Cell Culture System, has been employed as a system to investigate how renal progenitor cells respond to alterations in the mechanical cues within their microenvironment. Changes in cell phenotype, cytoskeleton organization, cell proliferation, cell adhesion and cell capacity for differentiation into podocytes were analyzed. Results In modeled microgravity conditions, renal progenitor cells showed altered cytoskeleton and focal adhesion organization associated with a reduction in cell proliferation, cell adhesion and spreading capacity. Moreover, mechanical forces appeared to be essential for renal progenitor differentiation into podocytes. Indeed, when renal progenitors were exposed to a differentiative agent in modeled microgravity conditions, it impaired the acquisition of a complex podocyte-like F-actin cytoskeleton and the expression of specific podocyte markers, such as nephrin and nestin. Importantly, the stabilization of the cytoskeleton with a calcineurin inhibitor, cyclosporine A, rescued the differentiation of renal progenitor cells into podocytes in modeled microgravity conditions. Conclusions Alterations in the organization of the renal progenitor cytoskeleton due to unloading conditions negatively affect the regenerative capacity of these cells. These findings strengthen the concept that changes in mechanical cues can initiate a pathophysiological process in the glomerulus, not only altering podocyte actin cytoskeleton, but also extending the detrimental effect to the renal progenitor population. This underscores the significance of the cytoskeleton as a druggable target for kidney diseases.

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Activation of Focal Adhesion Kinase Restores Simulated Microgravity-Induced Inhibition of Osteoblast Differentiation via Wnt/Β-Catenin Pathway

Cited by 11 publications

References 60 publications

Receptors Implicated in Microgravity-Induced Bone Loss

Receptors Implicated in Microgravity-Induced Bone Loss

Atp6v1h Deficiency Blocks Bone Loss in Simulated Microgravity Mice through the Fos-Jun-Src-Integrin Pathway

Modeled microgravity unravels the roles of mechanical forces in renal progenitor cell physiology

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