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

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Nicole R Gould ◽  
Katrina M Williams ◽  
Humberto C Joca ◽  
Olivia M Torre ◽  
James S Lyons ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Bone Formation ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Cell Lines ◽  
Mechanical Loading ◽  
Gaucher Disease ◽  
Mechanical Load ◽  
Lysosomal Degradation ◽  
Rodent Cell

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.

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

2020 ◽  
Author(s):  
Nicole R. Gould ◽  
Katrina M. Williams ◽  
Humberto C. Joca ◽  
Olivia M. Torre ◽  
James S. Lyons ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Bone Formation ◽  
Signaling Pathway ◽  
Mechanical Loading ◽  
Paradigm Shift ◽  
Gaucher Disease ◽  
Mechanical Load ◽  
Lysosomal Degradation ◽  
First Time

AbstractThe 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.

scholarly journals Design and Validation of Equiaxial Mechanical Strain Platform, EQUicycler, for 3D Tissue Engineered Constructs

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Mostafa Elsaadany ◽  
Matthew Harris ◽  
Eda Yildirim-Ayan
Keyword(s):  
Cell Lines ◽  
Mechanical Loading ◽  
Mechanical Load ◽  
Mechanical Strain ◽  
Three Dimensional ◽  
Cost Effective ◽  
Tissue Constructs ◽  
Tissue Systems

It is crucial to replicate the micromechanical milieu of native tissues to achieve efficacious tissue engineering and regenerative therapy. In this study, we introduced an innovative loading platform, EQUicycler, that utilizes a simple, yet effective, and well-controlled mechanism to apply physiologically relevant homogenous mechanical equiaxial strain on three-dimensional cell-embedded tissue scaffolds. The design of EQUicycler ensured elimination of gripping effects through the use of biologically compatible silicone posts for direct transfer of the mechanical load to the scaffolds. Finite Element Modeling (FEM) was created to understand and to quantify how much applied global strain was transferred from the loading mechanism to the tissue constructs. In vitro studies were conducted on various cell lines associated with tissues exposed to equiaxial mechanical loading in their native environment. In vitro results demonstrated that EQUicycler was effective in maintaining and promoting the viability of different musculoskeletal cell lines and upregulating early differentiation of osteoprogenitor cells. By utilizing EQUicycler, collagen fibers of the constructs were actively remodeled. Residing cells within the collagen construct elongated and aligned with strain direction upon mechanical loading. EQUicycler can provide an efficient and cost-effective tool to conduct mechanistic studies for tissue engineered constructs designed for tissue systems under mechanical loading in vivo.

Myeloma Cells Suppress Osteoblast Differentiation by Secreting a Soluble Wnt Inhibitor, sFRP-2.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2356-2356 ◽  
Author(s):  
Takashi Oshima ◽  
Masahiro Abe ◽  
Jin Asano ◽  
Tomoko Hara ◽  
Kenichi Kitazoe ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Osteoblast Differentiation ◽  
Wnt Signaling Pathway ◽  
Bone Destruction ◽  
Nodule Formation ◽  
Mrna Levels

Abstract Multiple myeloma (MM), a malignancy of plasma cells, develops in the bone marrow, and generates devastating bone destruction. Along with enhanced bone resorption, clinical evidence has also suggested suppression of bone formation as a contributing factor to the bone loss in MM. In contrast to recent understanding on mechanisms of osteolysis enahnced in MM, little is known about factors responsible for impaired bone formation. A canonical Wingless-type (Wnt) signaling pathway has recently been shown to play a critical role in osteoblast differentiation. Therefore, in the present study, we aimed to clarify mechanisms of suppression of osteoblast differentiation by MM cells with a particular focus on a canonical Wnt signaling pathway. Because several secreted Frizzled related protein (sFRP) and DKK family members are known as soluble Wnt antagonists, we first examined the expression of sFRP-1, 2 and 3 and DKK-1 in MM cell lines including U266, RPMI8226 and ARH77. All cell lines expressed sFRP-2 and sFRP-3 mRNA observed by RT-PCR. However, sFRP-1 was not expressed in any cell line, and Dkk-1 was expressed only in U266 cells at mRNA levels. We next conducted Western blot analyses for these factors and detected only sFRP-2 in immunoprecipitants of conditioned media as well as cell lysates of all these cell lines. However, no other factors were found at protein levels. Furthermore, sFRP-2 mRNA and protein expression was detected in most MM cells from patients with advanced or terminal stages of MM with bone destruction including plasma cell leukemia (3/4 and 8/10, respectively). In order to examine a biological role for sFRP-2, we added recombinant sFRP-2 to MC3T3-E1 cell culture together with BMP-2. Exogenous sFRP-2 partially suppressed alkaline phosphatase activity but almost completely mineralized nodule formation enhanced by BMP-2. Furthermore, sFRP-2 immunodepletion significantly restored mineralized nodule formation in MC3T3-E1 cells suppressed by RPMI8226 and ARH77 CM. These results suggest that sFRP-2 alone is able to suppress osteoblast differentiation induced by BMP-2 and that MM cell-derived sFRP-2 is among predominant factors responsible for defective bone formation in MM. Because MM cell-derived factors such as DKK-1, IGF-BP4 and IL-3 other than sFRP-2 have been implicated as an inhibitor of osteoblast differentiation, sFRP-2 may act alone or in combination with such other factors to potently suppress bone formation in MM. Taken together, MM cells may cause an imbalance of bone turnover with enhanced osteoclastic bone resorption and concomitantly suppressed bone formation, which leads to devastating destruction and a rapid loss of bone.

The skeletal responsiveness to mechanical loading is enhanced in mice with a null mutation in estrogen receptor-β

2007 ◽  
Vol 293 (2) ◽  
pp. E484-E491 ◽  
Author(s):  
L. K. Saxon ◽  
A. G. Robling ◽  
A. B. Castillo ◽  
S. Mohan ◽  
C. H. Turner
Keyword(s):  
Bone Formation ◽  
Mechanical Loading ◽  
Internal Control ◽  
Bone Cells ◽  
Mechanical Load ◽  
Formation Rate ◽  
Estrogen Signaling ◽  
Bone Formation Rate ◽  
Female Mice ◽  
Periosteal Surface

Mechanical loading caused by physical activity can stimulate bone formation and strengthen the skeleton. Estrogen receptors (ERs) play some role in the signaling cascade that is initiated in bone cells after a mechanical load is applied. We hypothesized that one of the ERs, ER-β, influences the responsiveness of bone to mechanical loads. To test our hypothesis, 16-wk-old male and female mice with null mutations in ER-β (ER-β−/−) had their right forelimbs subjected to short daily loading bouts. The loading technique used has been shown to increase bone formation in the ulna. Each loading bout consisted of 60 compressive loads within 30 s applied daily for 3 consecutive days. Bone formation was measured by first giving standard fluorochrome bone labels 1 and 6 days after loading and using quantitative histomorphometry to assess bone sections from the midshaft of the ulna. The left nonloaded ulna served as an internal control for the effects of loading. Mechanical loading increased bone formation rate at the periosteal bone surface of the mid-ulna in both ER-β−/− and wild-type (WT) mice. The ulnar responsiveness to loading was similar in male ER-β−/− vs. WT mice, but for female mice bone formation was stimulated more effectively in ER-β−/− mice ( P < 0.001). We conclude that estrogen signaling through ER-β suppresses the mechanical loading response on the periosteal surface of long bones.

scholarly journals Stimulation of Piezo1 by mechanical signals promotes bone anabolism

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Xuehua Li ◽  
Li Han ◽  
Intawat Nookaew ◽  
Erin Mannen ◽  
Matthew J Silva ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Ion Channel ◽  
Mechanical Loading ◽  
Fluid Shear Stress ◽  
Mechanical Load ◽  
Bone Matrix ◽  
Adult Mice ◽  
Sense And Respond ◽  
Stimulation Of

Mechanical loading, such as caused by exercise, stimulates bone formation by osteoblasts and increases bone strength, but the mechanisms are poorly understood. Osteocytes reside in bone matrix, sense changes in mechanical load, and produce signals that alter bone formation by osteoblasts. We report that the ion channel Piezo1 is required for changes in gene expression induced by fluid shear stress in cultured osteocytes and stimulation of Piezo1 by a small molecule agonist is sufficient to replicate the effects of fluid flow on osteocytes. Conditional deletion of Piezo1 in osteoblasts and osteocytes notably reduced bone mass and strength in mice. Conversely, administration of a Piezo1 agonist to adult mice increased bone mass, mimicking the effects of mechanical loading. These results demonstrate that Piezo1 is a mechanosensitive ion channel by which osteoblast lineage cells sense and respond to changes in mechanical load and identify a novel target for anabolic bone therapy.

Parathyroid hormone enhances osteogenesis in a rat model for extraosseous bone formation

1984 ◽  
Vol 104 (4_Supplb) ◽  
pp. S14 ◽  
Author(s):  
J. M. GOTTSWINTER ◽  
H. FLECHTNER ◽  
R. LÖWENSTEIN ◽  
R. ZIEGLER ◽  
G. DELLING
Keyword(s):  
Parathyroid Hormone ◽  
Bone Formation ◽  
Rat Model

scholarly journals Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xuehui Wang ◽  
Changle Ji ◽  
Jiashu Hu ◽  
Xiaochong Deng ◽  
Wenfang Zheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
Potential Biomarker

Abstract Background Circular RNAs (circRNAs), a novel class of endogenous RNAs, have shown to participate in the development of breast cancer (BC). Hsa_circ_0005273 is a circRNA generated from several exons of PTK2. However, the potential functional role of hsa_circ_0005273 in BC remains largely unknown. Here we aim to evaluate the role of hsa_circ_0005273 in BC. Methods The expression level of hsa_circ_0005273 and miR-200a-3p were examined by RT-qPCR in BC tissues and cell lines. The effect of knocking down hsa_circ_0005273 in BC cell lines were evaluated by examinations of cell proliferation, migration and cell cycle. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0005273 in BC. RNA immunoprecipitation assay, RNA probe pull-down assay, luciferase reporter assay and fluorescence in situ hybridization were conducted to confirm the relationship between hsa_circ_0005273, miR-200a-3p and YAP1. Results Hsa_circ_0005273 is over-expressed in BC tissues and cell lines, whereas miR-200a-3p expression is repressed. Depletion of hsa_circ_0005273 inhibited the progression of BC cells in vitro and in vivo, while overexpression of hsa_circ_0005273 exhibited the opposite effect. Importantly, hsa_circ_0005273 upregulated YAP1 expression and inactivated Hippo pathway via sponging miR-200a-3p to promote BC progression. Conclusions Hsa_circ_0005273 regulates the miR-200a-3p/YAP1 axis and inactivates Hippo signaling pathway to promote BC progression, which may become a potential biomarker and therapeutic target.

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