R-spondin 3 deletion induces Erk phosphorylation to enhance Wnt signaling and promote bone formation in the appendicular skeleton

Nagano, Kenichi; Yamana, Kei; Saito, Hiroaki; Kiviranta, Riku; Pedroni, Ana Clara Fagundes; Raval, Dhairya; Niehrs, Christof; Gori, Francesca; Baron, Roland

doi:10.7554/elife.84171

Cited by 10 publications

(10 citation statements)

References 72 publications

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“…S3, C and D). These data suggest that the role of TGR5 on bone microarchitecture differs based on skeletal location, which is in line with the recently described differential regulation of the axial and the appendicular skeleton 43,44 .…”

Section: Resultssupporting

confidence: 90%

The bile acid receptor TGR5 regulates the hematopoietic support capacity of the bone marrow niche

Alonso-Calleja,

Perino,

Schyrr

et al. 2023

Preprint

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The gut is an emerging regulator of bone marrow (BM) hematopoiesis and several signaling molecules are involved in this communication. Among them, bile acids (BAs), originally classified as lipid solubilizers, have emerged as powerful signaling molecules that act as a relay between the digestive system, the microbiota and the rest of the body. The signaling function of BAs relies on specific receptors, including Takeda-G-protein-receptor-5 (TGR5). TGR5 has potent regulatory effects in immune cells, but its effect on the BM as a primary immune organ remains unknown. Here, we investigated the BM of young mice and observed a significant reduction in bone marrow adipose tissue (BMAT) upon loss of TGR5, accompanied by an enrichment in BM adipocyte progenitors which translated into enhanced hematopoietic recovery upon transplantation. These findings open the possibility of modulating stromal hematopoietic support by acting on TGR5 signaling.SummaryThis work shows that TGR5 loss-of-function reduces regulated bone marrow adipose tissue and accelerates recovery upon bone marrow transplantation. These data highlight TGR5 as key player of the bone marrow microenvironment.

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Section: Resultssupporting

confidence: 90%

The bile acid receptor TGR5 regulates the hematopoietic support capacity of the bone marrow niche

Alonso-Calleja,

Perino,

Schyrr

et al. 2023

Preprint

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“…These observations suggest that the effect of adipogenic Dkk1 deletion on bone mass may be age dependent. Previous studies have shown that the role of Dkk1 in bone remodeling is complex and varies depending on the stage of skeletal development and the type of bone being examined ( 44 , 45 , 46 , 47 , 48 ). In addition, it is well-known that adipogenesis increases with aging and is linked with reduced bone formation ( 49 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of adipocyte-specific Dkk1 deletion on bone homeostasis and obesity-induced bone loss in male mice

Daamouch,

Thiele,

Hofbauer

et al. 2023

Endocrine Connections

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Obesity has been linked to reduced bone strength, and the canonical Wnt signaling pathway plays a crucial role in regulating mesenchymal stem cell differentiation into either osteoblasts or adipocytes. Previous research has shown that obesity-induced upregulation of Dkk1, a Wnt inhibitor produced by osteoblasts, drives bone loss. However, the role of adipocyte-produced Dkk1 in bone remodeling and obesity-induced bone loss remains unclear. In this study, we investigated the influence of adipogenic Dkk1 on bone homeostasis and obesity-induced bone loss in mice. Using tamoxifen administration, we induced deletion of Dkk1 in adipocytes in male Dkk1fl/fl;AdipoQcreERT2 (Dkk1 cKO) mice and fed Dkk1fl/fl;AdipoQcre-positive mice and controls a high-fat diet (HFD) for 12 weeks. Bone and fat mass were analyzed at 12 and 20 weeks of age. In this study we found that 12-week-old male mice without adipogenic Dkk1 had a significant increase in trabecular bone volume in the vertebrae and femoral bones. However, there was no difference in bone volume between controls and Dkk1fl/fl;AdipoQcre-positive mice at 20 weeks of age. Additionally, Dkk1fl/fl;AdipoQcre-positive mice were not protected from HFD-induced bone loss. Even though Sost, another important Wnt inhibitor, was expressed at lower levels in bone from Dkk1-deficient mice fed with HFD compared to Dkk1-sufficient mice, this did not prevent the HFD-induced suppression of bone formation. Therefore, adipogenic Dkk1 may play a transient role in bone mass regulation during adolescence, but it does not contribute to bone homeostasis or obesity-induced bone loss later in life.

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“…65 ERK phosphorylation is pivotal to osteoblast differentiation and the balance between bone formation and resorption. 66 Bandow et al showed on osteoblasts angiotensin type 1 (AT1) inhibitors could counteract LIPUS-induced ERK phosphorylation and RANKL expression. 67 However, it is unclear whether the AT1 inhibitor can reverse the LIPUS-induced upregulation of COX-2 and PEG2.…”

Section: Mechanism Of Lipus On Fracture Healingmentioning

confidence: 99%

“…Koukubu et al found LIPUS treatment in mouse osteoblasts upregulated COX‐2 mRNA expression and consequently higher PGE2 production 55 through presumably the integrin/FAK/PI3K/Akt and ERK signaling pathways 65 . ERK phosphorylation is pivotal to osteoblast differentiation and the balance between bone formation and resorption 66 . Bandow et al showed on osteoblasts angiotensin type 1 (AT1) inhibitors could counteract LIPUS‐induced ERK phosphorylation and RANKL expression 67 .…”

Section: Mechanism Of Lipus On Fracture Healingmentioning

confidence: 99%

Latest Progress of LIPUS in Fracture Healing

Guo,

Lv,

Lin

et al. 2024

J of Ultrasound Medicine

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The use of low‐intensity pulsed ultrasound (LIPUS) for promoting fracture healing has been Food and Drug Administration (FDA)‐approved since 1994 due to largely its non‐thermal effects of sound flow sound radiation force and so on. Numerous clinical and animal studies have shown that LIPUS can accelerate the healing of fresh fractures, nonunions, and delayed unions in pulse mode regardless of LIPUS devices or circumstantial factors. Rare clinical studies show limitations of LIPUS for treating fractures with intramedullary nail fixation or low patient compliance. The biological effect is achieved by regulating various cellular behaviors involving mesenchymal stem/stromal cells (MSCs), osteoblasts, chondrocytes, and osteoclasts and with dose dependency on LIPUS intensity and time. Specifically, LIPUS promotes the osteogenic differentiation of MSCs through the ROCK‐Cot/Tpl2‐MEK–ERK signaling. Osteoblasts, in turn, respond to the mechanical signal of LIPUS through integrin, angiotensin type 1 (AT1), and PIEZO1 mechano‐receptors, leading to the production of inflammatory factors such as COX‐2, MCP‐1, and MIP‐1β fracture repair. LIPUS also induces CCN2 expression in chondrocytes thereby coordinating bone regeneration. Finally, LIPUS suppresses osteoclast differentiation and gene expression by interfering with the ERK/c‐Fos/NFATc1 cascade. This mini‐review revisits the known effects and mechanisms of LIPUS on bone fracture healing and strengthens the need for further investigation into the underlying mechanisms.

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R-spondin 3 deletion induces Erk phosphorylation to enhance Wnt signaling and promote bone formation in the appendicular skeleton

Cited by 10 publications

References 72 publications

The bile acid receptor TGR5 regulates the hematopoietic support capacity of the bone marrow niche

The bile acid receptor TGR5 regulates the hematopoietic support capacity of the bone marrow niche

Effects of adipocyte-specific Dkk1 deletion on bone homeostasis and obesity-induced bone loss in male mice

Latest Progress of LIPUS in Fracture Healing

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