scholarly journals Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass

2018 ◽  
Author(s):  
Bo Shen ◽  
Kristy Vardy ◽  
Payton Hughes ◽  
Alpaslan Tasdogan ◽  
Zhiyu Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Bone Marrow Stromal Cells ◽  
Wnt Pathway ◽  
Leptin Receptor ◽  
Pathway Activation ◽  
Osteogenic Response ◽  
Skeletal Bone ◽  
Adult Bone ◽  
Deficient Mice

AbstractWe previously discovered a new osteogenic growth factor that is required to maintain adult skeletal bone mass, Osteolectin/Clec11a. Osteolectin acts on Leptin Receptor+(LepR+) skeletal stem cells and other osteogenic progenitors in bone marrow to promote their differentiation into osteoblasts. Here we identity a receptor for Osteolectin, α11 integrin, which is expressed by LepR+cells and osteoblasts. α11β1 integrin binds Osteolectin with nanomolar affinity and is required for the osteogenic response to Osteolectin. Deletion ofItga11(which encodes α11) from mouse and human bone marrow stromal cells impaired osteogenic differentiation and blocked their response to Osteolectin. LikeOsteolectindeficient mice,Lepr-cre;Itga11fl/flmice appeared grossly normal but exhibited reduced osteogenesis and accelerated bone loss during aging. Osteolectin binding to α11β1 promoted Wnt pathway activation, which was necessary for the osteogenic response to Osteolectin. This reveals a new mechanism for maintenance of adult bone mass: Wnt pathway activation by Osteolectin/α11β1 signaling.

scholarly journals Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Bo Shen ◽  
Kristy Vardy ◽  
Payton Hughes ◽  
Alpaslan Tasdogan ◽  
Zhiyu Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Bone Marrow Stromal Cells ◽  
Wnt Pathway ◽  
Leptin Receptor ◽  
Pathway Activation ◽  
Osteogenic Response ◽  
Skeletal Bone ◽  
Adult Bone ◽  
Deficient Mice

We previously discovered a new osteogenic growth factor that is required to maintain adult skeletal bone mass, Osteolectin/Clec11a. Osteolectin acts on Leptin Receptor+ (LepR+) skeletal stem cells and other osteogenic progenitors in bone marrow to promote their differentiation into osteoblasts. Here we identify a receptor for Osteolectin, integrin α11, which is expressed by LepR+ cells and osteoblasts. α11β1 integrin binds Osteolectin with nanomolar affinity and is required for the osteogenic response to Osteolectin. Deletion of Itga11 (which encodes α11) from mouse and human bone marrow stromal cells impaired osteogenic differentiation and blocked their response to Osteolectin. Like Osteolectin deficient mice, Lepr-cre; Itga11fl/fl mice appeared grossly normal but exhibited reduced osteogenesis and accelerated bone loss during adulthood. Osteolectin binding to α11β1 promoted Wnt pathway activation, which was necessary for the osteogenic response to Osteolectin. This reveals a new mechanism for maintenance of adult bone mass: Wnt pathway activation by Osteolectin/α11β1 signaling.

scholarly journals The effect of parathyroid hormone on osteogenesis is mediated partly by osteolectin

2021 ◽  
Vol 118 (25) ◽  
pp. e2026176118
Author(s):  
Jingzhu Zhang ◽  
Adi Cohen ◽  
Bo Shen ◽  
Liming Du ◽  
Alpaslan Tasdogan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Parathyroid Hormone ◽  
Bone Formation ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Wnt Pathway ◽  
Leptin Receptor ◽  
Marrow Stromal Cells ◽  
Pathway Activation ◽  
Osteogenic Response

We previously described a new osteogenic growth factor, osteolectin/Clec11a, which is required for the maintenance of skeletal bone mass during adulthood. Osteolectin binds to Integrin α11 (Itga11), promoting Wnt pathway activation and osteogenic differentiation by leptin receptor+ (LepR+) stromal cells in the bone marrow. Parathyroid hormone (PTH) and sclerostin inhibitor (SOSTi) are bone anabolic agents that are administered to patients with osteoporosis. Here we tested whether osteolectin mediates the effects of PTH or SOSTi on bone formation. We discovered that PTH promoted Osteolectin expression by bone marrow stromal cells within hours of administration and that PTH treatment increased serum osteolectin levels in mice and humans. Osteolectin deficiency in mice attenuated Wnt pathway activation by PTH in bone marrow stromal cells and reduced the osteogenic response to PTH in vitro and in vivo. In contrast, SOSTi did not affect serum osteolectin levels and osteolectin was not required for SOSTi-induced bone formation. Combined administration of osteolectin and PTH, but not osteolectin and SOSTi, additively increased bone volume. PTH thus promotes osteolectin expression and osteolectin mediates part of the effect of PTH on bone formation.

scholarly journals The nucleocytoplasmic shuttling protein CIZ reduces adult bone mass by inhibiting bone morphogenetic protein–induced bone formation

2005 ◽  
Vol 201 (6) ◽  
pp. 961-970 ◽  
Author(s):  
Mikihiko Morinobu ◽  
Tetsuya Nakamoto ◽  
Kazunori Hino ◽  
Kunikazu Tsuji ◽  
Zhong-Jian Shen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Bone Mass ◽  
Mrna Expression ◽  
Bone Marrow Cells ◽  
Nucleocytoplasmic Shuttling ◽  
Morphogenetic Protein ◽  
Adult Bone ◽  
Deficient Mice

Osteoporosis is a major health problem; however, the mechanisms regulating adult bone mass are poorly understood. Cas-interacting zinc finger protein (CIZ) is a nucleocytoplasmic shuttling protein that localizes at cell adhesion plaques that form where osteoblasts attach to substrate. To investigate the potential role of CIZ in regulating adult bone mass, we examined the bones in CIZ-deficient mice. Bone volume was increased and the rates of bone formation were increased in CIZ-deficient mice, whereas bone resorption was not altered. CIZ deficiency enhanced the levels of mRNA expression of genes encoding proteins related to osteoblastic phenotypes, such as alkaline phosphatase (ALP) as well as osterix mRNA expression in whole long bones. Bone marrow cells obtained from the femora of CIZ-deficient mice revealed higher ALP activity in culture and formed more mineralized nodules than wild-type cells. CIZ deficiency enhanced bone morphogenetic protein (BMP)–induced osteoblastic differentiation in bone marrow cells in cultures, indicating that BMP is the target of CIZ action. CIZ deficiency increased newly formed bone mass after femoral bone marrow ablation in vivo. Finally, BMP-2–induced bone formation on adult mouse calvariae in vivo was enhanced by CIZ deficiency. These results establish that CIZ suppresses the levels of adult bone mass through inhibition of BMP-induced activation of osteoblasts.

scholarly journals BMP3 Suppresses Osteoblast Differentiation of Bone Marrow Stromal Cells via Interaction with Acvr2b

2012 ◽  
Vol 26 (1) ◽  
pp. 87-94 ◽  
Author(s):  
Shoichiro Kokabu ◽  
Laura Gamer ◽  
Karen Cox ◽  
Jonathan Lowery ◽  
Kunikazu Tsuji ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Bone Mass ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Physiological Role ◽  
Bmp Signaling ◽  
Marrow Stromal Cells ◽  
Colony Forming Unit ◽  
Adult Bone

Abstract Enhancing bone morphogenetic protein (BMP) signaling increases bone formation in a variety of settings that target bone repair. However, the role of BMP in the maintenance of adult bone mass is not well understood. Targeted disruption of BMP3 in mice results in increased trabecular bone formation, whereas transgenic overexpression of BMP3 in skeletal cells leads to spontaneous fracture, consistent with BMP3 having a negative role in bone mass regulation. Here we investigate the importance of BMP3 as a mediator of BMP signaling in the adult skeleton. We find that osteoblasts (OBL) and osteocytes are the source of BMP3 in adult bone. Using in vitro cultures of primary bone marrow stromal cells, we show that overexpression of BMP3 suppresses OBL differentiation, whereas loss of BMP3 increases colony-forming unit fibroblasts and colony-forming unit OBL. The ability of BMP3 to affect OBL differentiation is due to its interaction with activin receptor type 2b (Acvr2b) because knockdown of endogenous Acvr2b in bone marrow stromal cells reduces the suppressive effect of BMP3 on OBL differentiation. These findings best fit a model in which BMP3, produced by mature bone cells, acts to reduce BMP signaling through Acvr2b in skeletal progenitor cells, limiting their differentiation to mature OBL. Our data further support the idea that endogenous BMPs have a physiological role in regulating adult bone mass.

Abstract 1129: Obesity-related Elevations in Soluble P-selectin are Derived From Endothelium and Dependent on Expression of Leukocyte P-selectin Glycoprotein Ligand-1

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kevin J Wickenheiser ◽  
Peter F Bodary ◽  
Kristina Bahrou ◽  
Daniel T Eitzman
Keyword(s):  
Bone Marrow ◽  
Body Weight ◽  
Leptin Receptor ◽  
The Body ◽  
Wild Type ◽  
Post Transplant ◽  
Time Period ◽  
Increased Risk ◽  
Soluble P ◽  
Deficient Mice

Background : Obesity is associated with proinflammatory changes and an increased risk for vascular disease complications. The tissue source and mechanism by which soluble P-selectin (sPsel) is generated in obesity are unclear. Methods and Results : Soluble p-selectin (sPsel) levels were measured in the circulation from lean wild type and obese leptin receptor deficient mice (LepR−/−) at 4 and 10 weeks of age. In wild-type mice body weight increases from 13+/−2 to 20+/−3 grams over this time period while the body weight increases from 15+/−2 to 38+/−5 grams in LepR−/− mice. At 4 weeks of age sPsel levels were 103+/−8mg/mL in wild-type mice vs. 138+/−9 ng/mL in LepR−/− mice, p=0.048. By 10 wks of age sPsel increased to 112 +/− 2 in wild-type mice and 182 +/− 9 in LepR−/− mice, p=0.00005. In order to determine if the obesity-induced rise in sPsel is regulated by leukocyte Psgl-1, bone marrow transplantation was performed from Psgl+/+ or Psgl−/− donors into irradiated LepR−/−recipients. At 4 weeks post-transplant, sPsel levels were 166 +/−6 ng/mL in LepR−/− mice receiving Psgl+/+ marrow and 45 +/− 4 ng/mL in LepR−/− mice receiving Psgl−/− marrow, p=0.0000004. In order to determine if the sPsel in LepR−/− mice originated from the endothelium versus platelets, we transplanted Psel−/− bone marrow into irradiated LepR−/−mice. At 4 weeks post transplant, sPsel levels were 153 +/−3 ng/mL in LepR−/− mice receiving Psel−/− bone marrow and were not significantly different from LepR−/− mice receiving Psel+/+ bone marrow (166 +/−6 ng/mL, p=0.06). By 10 weeks post transplant, mice gained even more weight and levels were 377+/−51 ng/mL in LepR−/− mice receiving Psel+/+ bone marrow and 370+/−73 ng/mL in LepR−/− mice receiving Psel−/− bone marrow, p=0.87. Conclusions : These data suggest that the increase in sPsel observed in obesity is primarily derived from the endothelium and that this process is regulated by leukocyte Psgl-1.

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