scholarly journals Osteoblast-Specific Wnt Secretion is Required for Skeletal Homeostasis and Loading-Induced Bone Formation in Adult Mice

2021 ◽  
Author(s):  
Lisa Y. Lawson ◽  
Michael D. Brodt ◽  
Nicole Migotsky ◽  
Christopher Chermside-Scabbo ◽  
Ramya Palaniappan ◽  
...  
Keyword(s):  
Bone Formation ◽  
Mechanical Loading ◽  
Bone Homeostasis ◽  
Genetic Approach ◽  
Anabolic Response ◽  
Adult Mice ◽  
Wnt Ligands ◽  
Skeletal Homeostasis ◽  
Adult Bone ◽  
Systemic Drug

AbstractWnt signaling is critical to many aspects of skeletal regulation, but the importance of Wnt ligands in adult bone homeostasis and the anabolic response to mechanical loading is not well documented. We inhibited Wnt ligand secretion in adult (5-mo) mice using a systemic (drug) and a bone-targeted (genetic) approach, and subjected them to axial tibial loading to induce lamellar bone formation. Mice treated with the porcupine inhibitor WNT974 exhibited a decrease in bone formation in non-loaded limbs as well as a 54% decline in the periosteal bone formation response to tibial loading. Similarly, within 1-2 weeks of Wls deletion in osteoblasts (Osx-CreERT2;WlsF/F mice), skeletal homeostasis was altered with decreased bone formation and increased resorption, and the anabolic response to loading was reduced 65% compared to control (WlsF/F). These findings establish a requirement for Wnt ligand secretion by osteoblasts for adult bone homeostasis and the anabolic response to mechanical loading.

scholarly journals Bmp2 conditional knockout in osteoblasts and endothelial cells does not impair bone formation after injury or mechanical loading in adult mice

Bone ◽  
2015 ◽  
Vol 81 ◽  
pp. 533-543 ◽  
Author(s):  
Sarah Howe McBride-Gagyi ◽  
Jennifer A. McKenzie ◽  
Evan G. Buettmann ◽  
Michael J. Gardner ◽  
Matthew J. Silva
Keyword(s):  
Endothelial Cells ◽  
Bone Formation ◽  
Mechanical Loading ◽  
Conditional Knockout ◽  
Adult Mice

Osteocytes and WNT: the Mechanical Control of Bone Formation

2010 ◽  
Vol 89 (4) ◽  
pp. 331-343 ◽  
Author(s):  
C. Galli ◽  
G. Passeri ◽  
G.M. Macaluso
Keyword(s):  
Mechanical Properties ◽  
Bone Formation ◽  
Cell Fate ◽  
Mechanical Loading ◽  
Osteoblastic Differentiation ◽  
Mechanical Stimuli ◽  
Master Regulators ◽  
Bone Maintenance ◽  
Skeletal Homeostasis ◽  
Encoding Gene

Mechanical loading is of pivotal importance in the maintenance of skeletal homeostasis, but the players involved in the transduction of mechanical stimuli to promote bone maintenance have long remained elusive. Osteocytes, the most abundant cells in bone, possess mechanosensing appendices stretching through a system of bone canaliculi. Mechanical stimulation plays an important role in osteocyte survival and hence in the preservation of bone mechanical properties, through the maintenance of bone hydratation. Osteocytes can also control the osteoblastic differentiation of mesenchymal precursors in response to mechanical loading by modulating WNT signaling pathways, essential regulators of cell fate and commitment, through the protein sclerostin. Mutations of Sost, the sclerostin-encoding gene, have dramatic effects on the skeleton, indicating that osteocytes may act as master regulators of bone formation and localized bone remodeling. Moreover, the development of sclerostin inhibitors is opening new possibilities for bone regeneration in orthopedics and the dental field.

scholarly journals Osteoblast‐Specific Wnt Secretion is Required for Skeletal Homeostasis and Loading‐Induced Bone Formation in Adult Mice

2021 ◽  
Author(s):  
Lisa Y. Lawson ◽  
Michael D. Brodt ◽  
Nicole Migotsky ◽  
Christopher J. Chermside‐Scabbo ◽  
Ramya Palaniappan ◽  
...  
Keyword(s):  
Bone Formation ◽  
Adult Mice ◽  
Skeletal Homeostasis

scholarly journals Physiological Bone Remodeling: Systemic Regulation and Growth Factor Involvement

Physiology ◽  
2016 ◽  
Vol 31 (3) ◽  
pp. 233-245 ◽  
Author(s):  
Jawed A. Siddiqui ◽  
Nicola C. Partridge
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Recent Work ◽  
Bone Homeostasis ◽  
Mineral Homeostasis ◽  
Two Phases ◽  
Adult Bone

Bone remodeling is essential for adult bone homeostasis. It comprises two phases: bone formation and resorption. The balance between the two phases is crucial for sustaining bone mass and systemic mineral homeostasis. This review highlights recent work on physiological bone remodeling and discusses our knowledge of how systemic and growth factors regulate this process.

scholarly journals Coordinated transcriptional regulation of bone homeostasis by Ebf1 and Zfp521 in both mesenchymal and hematopoietic lineages

2013 ◽  
Vol 210 (5) ◽  
pp. 969-985 ◽  
Author(s):  
Riku Kiviranta ◽  
Kei Yamana ◽  
Hiroaki Saito ◽  
Daniel K. Ho ◽  
Julius Laine ◽  
...  
Keyword(s):  
Bone Formation ◽  
Transcriptional Activity ◽  
Bone Homeostasis ◽  
Targeted Deletion ◽  
Bone Phenotype ◽  
Adult Mice ◽  
Transcriptional Coregulator ◽  
Early B Cell Factor ◽  
Coordinated Effects

Bone homeostasis is maintained by the coupled actions of hematopoietic bone-resorbing osteoclasts (OCs) and mesenchymal bone-forming osteoblasts (OBs). Here we identify early B cell factor 1 (Ebf1) and the transcriptional coregulator Zfp521 as components of the machinery that regulates bone homeostasis through coordinated effects in both lineages. Deletion of Zfp521 in OBs led to impaired bone formation and increased OB-dependent osteoclastogenesis (OC-genesis), and deletion in hematopoietic cells revealed a strong cell-autonomous role for Zfp521 in OC progenitors. In adult mice, the effects of Zfp521 were largely caused by repression of Ebf1, and the bone phenotype of Zfp521+/− mice was rescued in Zfp521+/−:Ebf1+/− mice. Zfp521 interacted with Ebf1 and repressed its transcriptional activity. Accordingly, deletion of Zfp521 led to increased Ebf1 activity in OBs and OCs. In vivo, Ebf1 overexpression in OBs resulted in suppressed bone formation, similar to the phenotype seen after OB-targeted deletion of Zfp521. Conversely, Ebf1 deletion led to cell-autonomous defects in both OB-dependent and cell-intrinsic OC-genesis, a phenotype opposite to that of the Zfp521 knockout. Thus, we have identified the interplay between Zfp521 and Ebf1 as a novel rheostat for bone homeostasis.

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.

scholarly journals CYLD, a Mechanosensitive Deubiquitinase, Regulates TGFβ Signaling in Load-Induced Bone Formation

2019 ◽  
Author(s):  
Jacqueline Nguyen ◽  
Ramin Massoumi ◽  
Tamara Alliston
Keyword(s):  
Bone Formation ◽  
Mechanical Loading ◽  
Mechanical Stimulation ◽  
Mrna Levels ◽  
Bone Homeostasis ◽  
Tgfβ Signaling ◽  
Protein Levels ◽  
Tgfβ Pathway ◽  
Dependent Mechanism

AbstractMany signaling pathways involved in bone homeostasis also participate in the anabolic response of bone to mechanical loading. For example, TGFβ signaling coordinates the maintenance of bone mass and bone quality through its effects on osteoblasts, osteoclasts, and osteocytes. TGFβ signaling is also essential for the mechanosensitive formation of new bone. However, the mechanosensitive mechanisms controlling TGFβ signaling in osteocytes remain to be determined, particularly those that integrate TGFβ signaling with other early responses to mechanical stimulation. Here, we used an in vivo mouse hindlimb loading model to identify mechanosensitive molecules in the TGFβ pathway, and MLOY4 cells to evaluate their interactions with the prostaglandin E2 (PGE2) pathway, which is well-known for its rapid response to mechanical stimulation and its role in bone anabolism. Although mRNA levels for several TGFβ ligands, receptors, and effectors were unchanged, the level of phosphorylated Smad3 (pSmad3) was reduced in tibial bone as early as 3 hrs after early mechanical stimulation. We found that PGE2 and its receptor, EP2, repress pSmad3 levels and transactivation of Serpine1 in osteocytes. PGE2 and EP2 control the level of pSmad3 through a proteasome-dependent mechanism that relies on the deubiquitinase CYLD. CYLD protein levels were also reduced in the tibiae within 3 hrs of mechanical loading. Using CYLD-deficient mice, we found that CYLD is required for the rapid load-mediated repression of pSmad3 and for load-induced bone formation. These data introduce CYLD as a mechanosensitive deubiquitinase that participates in the PGE2-dependent repression of TGFβ signaling in osteocytes.

scholarly journals Transgenic Overexpression of Ephrin B1 in Bone Cells Promotes Bone Formation and an Anabolic Response to Mechanical Loading in Mice

PLoS ONE ◽  
2013 ◽  
Vol 8 (7) ◽  
pp. e69051 ◽  
Author(s):  
Shaohong Cheng ◽  
Chandrasekhar Kesavan ◽  
Subburaman Mohan ◽  
Xuezhong Qin ◽  
Catrina M. Alarcon ◽  
...  
Keyword(s):  
Bone Formation ◽  
Mechanical Loading ◽  
Bone Cells ◽  
Anabolic Response

scholarly journals The p38α MAPK Function in Osteoprecursors Is Required for Bone Formation and Bone Homeostasis in Adult Mice

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e102032 ◽  
Author(s):  
Edgardo Rodríguez-Carballo ◽  
Beatriz Gámez ◽  
Lara Sedó-Cabezón ◽  
Manuela Sánchez-Feutrie ◽  
Antonio Zorzano ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Homeostasis ◽  
Adult Mice ◽  
P38α Mapk

scholarly journals The Role of BMP Signaling in Osteoclast Regulation

2021 ◽  
Vol 9 (3) ◽  
pp. 24
Author(s):  
Brian Heubel ◽  
Anja Nohe
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Bone Diseases ◽  
Bmp Signaling ◽  
Bone Homeostasis ◽  
Direct Stimulation ◽  
Federal Drug Administration ◽  
Bmp Pathway ◽  
Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

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