CHIP regulates bone mass by targeting multiple TRAF family members in bone marrow stromal cells

Abstract Objectives Obesity is detrimental to bone health in humans and in high-fat diet-induced obese animals. Bone marrow osteoblasts and adipocytes are derived from a common mesenchymal stem cell and have a reciprocal relationship. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a regulator for adipocyte differentiation, may be a potential target for reducing obesity and increasing bone mass. This study tested the hypothesis that bone-specific PPAR gamma conditional knockout (cKO), via deletion of PPAR gamma gene from bone marrow stromal cells (BMSC) using Osterix 1 (Osx1)-Cre, would prevent high-fat diet-induced bone deterioration in mice. Methods PPAR gamma cKO (PPAR gammafl/fl: Osx1–Cre) and floxed littermate control (PPAR gammafl/fl Osx1-P-Cre-) mice at 6-wk-old were randomly assigned to 4 groups (n = 12/group, 6 male and 6 female) and fed ad libitum either a normal-fat purified diet (NF, 3.85 kcal/g, 10% energy as fat) or a high-fat diet (HF, 4.73 kcal/g) for 6 mo. Bone structure, body composition, and serum bone-related cytokines were measured. Results Compared to the NF diet, the HF diet increased body mass and fat mass (P < 0.05) but not lean mass. The HF diet also decreased tibial and lumbar vertebrae trabecular volume/total volume (BV/TV) and bone mineral density (BMD) in both control and PPAR gamma cKO mice. PPAR gamma cKO mice had lower body fat mass and lean mass than control mice. PPAR gamma cKO mice had greater tibial trabecular BV/TV, trabecular number, connectivity density, and BMD and lower structure model index, compared to control mice. None of trabecular bone parameters at 2nd lumbar vertebrae was affected by genotype. PPAR gamma cKO mice had lower cortical medullary area, compared to control mice. PPAR gamma cKO mice had lower (P < 0.01) serum concentration of leptin and higher (P < 0.05) concentration of osteocalcin, compared with control mice. Conclusions These data indicate that PPAR gamma has site-specific impact on bone structure in mice and that knockout PPAR gamma in BMSC increased bone mass in tibia likely through increased osteoblastogenesis. However, PPAR gamma disruption in BMSC did not prevent high-fat diet-induced bone deterioration in mice. Funding Sources USDA-ARS #3062-51,000-053-00D.

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Biglycan (Bgn) and fibromodulin (Fmod) modulate bone mass by regulating osteoclast differentiation through bone marrow stromal cells

Bone ◽

10.1016/j.bone.2008.08.058 ◽

2008 ◽

Vol 43 ◽

pp. S58

Author(s):

Yanming Bi ◽

Tina Kilts ◽

Alfred Griffin ◽

Theresa Hefferan ◽

Fatima Syed-Picard ◽

...

Keyword(s):

Bone Marrow ◽

Bone Mass ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Osteoclast Differentiation ◽

Marrow Stromal Cells

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

Molecular Endocrinology ◽

10.1210/me.2011-1168 ◽

2012 ◽

Vol 26 (1) ◽

pp. 87-94 ◽

Cited By ~ 68

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.

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The Involvement of NF-κB Subunits in the Interaction Between CLL-B Cells and Bone Marrow Stromal Cells

Blood ◽

10.1182/blood.v118.21.4590.4590 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4590-4590

Author(s):

Aining Sun ◽

Guo Feng ◽

Jingjing Xu ◽

Wenjuan Wang ◽

Wu Depei

Keyword(s):

Bone Marrow ◽

B Cells ◽

Mrna Expression ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Family Members ◽

Proteasome Inhibitors ◽

Marrow Stromal Cells ◽

Protein Levels ◽

Relative Mrna Expression

Abstract Abstract 4590 Objective: To investigate the function of NF-κB signaling pathway in the interaction between chronic lymphocytic leukemia B cells and bone marrow stromal cells. Method: The expression of NF-κB family members at mRNA and protein levels were examined by quantitative RT-PCR and Western bloting analyses individualy, and the differences between CLL-human bone marrow stromal cell (hBMSC) and non-CLL-hBMSC were investigated with the methods above. Cell death was measured by flow cytometry analysis after B-CLL cells were co-cultured with hBMSC and treated with proteasome inhibitors. The changes of NF-κB expression at the protein levels were examined by Western bloting after co-culture experiment. Result: The expression of NF-κB family members turned out to be heterogeneous at both mRNA and protein levels in B-CLL cells, and the members demonstrated a different κB-DNA binding activities. The mRNA expression of NF-κB family members in B-CLL cells was shown at a remarkable higher level than that of the controls. The relative mRNA expression of relA was 0.0214±0.012, whereas it was 0.0130±0.012 for the controls of CD19 positive cells. The relative mRNA expression of p50 and p52 were 66.0860±21.649 and 0.0208±0.011 respectively, and the corresponding expression of CD19 positive cells were 24.8440±9.749 and 0.0065±0.002. The differences were statistically significant. There was no notable difference between CLL-hBMSC and Non-CLL-hBMSC. hBMSC protected B-CLL cells against the proteasome inhibitors and facilitated the survival of B-CLL cells. Conclusion: NF-κB expression is heterogeneous in bone marrow B-CLL cells. There is no significant difference between CLL-hBMSC and non-CLL-hBMSC. hBMSC can protect the survival of B-CLL cells dependending on the endogenous NF-κB activity. hBMSC can increase the drug resistance of B-CLL cells to proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.

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