Association of Bone Mineral Density with a Polymorphism of the Peroxisome Proliferator-Activated Receptor γ Gene: PPARγ Expression in Osteoblasts

Ogawa, Sumito; Urano, Tomohiko; Hosoi, Takayuki; Miyao, Mariko; Hoshino, Shotaro; Fujita, Masayo; Shiraki, Masataka; Orimo, Hajime; Ouchi, Yasuyoshi; Inoue, Satoshi

doi:10.1006/bbrc.1999.0896

Cited by 101 publications

(71 citation statements)

References 36 publications

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“…Our findings are also in accordance with a previous study showing that decreased igf1 expression and translation in MSCs associated with activation of PPAR␥ transcription factor and suppressed bone formation by regulating OB/adipocyte lineage allocation to enhance BM adipogenesis (30). Low IGF-1 associated with polymorphisms in the human ppar␥ gene has been linked to low bone mineral density and obesity (31,32). A recent study also demonstrated that reducing IGF-1 by activating ppar␥ in mice with rosiglitazone increased BM adiposity and suppressed bone formation, another indication of the importance of BM cell fate (33).…”

Section: Discussionsupporting

confidence: 92%

The Insulin-like Growth Factor-1 Binding Protein Acid-labile Subunit Alters Mesenchymal Stromal Cell Fate

Fritton

Kawashima

Mejía

et al. 2010

Journal of Biological Chemistry

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Age-related osteoporosis is accompanied by an increase in marrow adiposity and a reduction in serum insulin-like growth factor-1 (IGF-1) and the binding proteins that stabilize IGF-1. To determine the relationship between these proteins and bone marrow adiposity, we evaluated the adipogenic potential of marrow-derived mesenchymal stromal cells (MSCs) from mice with decreased serum IGF-1 due to knockdown of IGF-1 production by the liver or knock-out of the binding proteins. We employed 10 -16-week-old, liver-specific IGF-1-deficient, IGFBP-3 knockout (BP3KO) and acid-labile subunit knock-out (ALSKO) mice. We found that expression of the late adipocyte differentiation marker peroxisome proliferator-activated receptor ␥ was increased in marrow isolated from ALSKO mice. When induced with adipogenic media, MSC cultures from ALSKO mice revealed a significantly greater number of differentiated adipocytes compared with controls. MSCs from ALSKO mice also exhibited decreased alkaline-phosphatase positive colony size in cultures that were stimulated with osteoblast differentiation media. These osteoblast-like cells from ALSKO mice failed to induce osteoclastogenesis of control cells in co-culture assays, indicating that impairment of IGF-1 complex formation with ALS in bone marrow alters cell fate, leading to increased adipogenesis.In bone marrow (BM), 3 cell fate determination is dependent on the local microenvironment. Cell-cell interactions, hormones, and cytokines all play a role in establishing the timing and magnitude of lineage commitment and cellular differentiation into adipocytes, osteoblasts (OBs), or osteoclasts (OCs).OCs and OBs, cells that are essential for bone remodeling, differentiate from stem cells of hematopoietic and mesenchymal origin, respectively (1). Marrow adipocytes are also thought to arise from mesenchymal precursor cells. Interestingly, osteoclastogenesis is closely associated with both osteoblastogenesis and adipogenesis. In the former, OBs produce receptor activator of the NF-␤ ligand (RANKL) and osteoprotegerin, two critical factors in the OC differentiation scheme. In the latter, mature adipocytes secrete adipokines and cytokines that promote OC recruitment and differentiation (2). Moreover, in many circumstances, commitment of mesenchymal stromal cells (MSCs) down the adipogenic lineage precludes OB differentiation. Thus, several lines of evidence support the tenet that osteoclastogenesis is related to adipogenesis in the BM (3, 4).Increased osteoclastogenesis and BM adiposity are hallmarks of age-related osteoporosis, a syndrome associated with rapid bone loss and architectural deterioration that predisposes individuals to fracture (5). Significant reductions in serum insulinlike growth factor (IGF-1) levels and osteogenesis are also associated with aging (6, 7). However, the relationship between bioavailable IGF-1 and BM cell fate is largely unknown. Recent studies in animal models and humans have demonstrated an important role for the growth hormone/IGF-1 axis in bone growth and remod...

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Section: Discussionsupporting

confidence: 92%

The Insulin-like Growth Factor-1 Binding Protein Acid-labile Subunit Alters Mesenchymal Stromal Cell Fate

Fritton

Kawashima

Mejía

et al. 2010

Journal of Biological Chemistry

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“…Adipose tissue is a source of inflammatory cytokines and PPARG is widely associated with type II diabetes and concomitant obesity. Association between PPARG and lower BMD has previously been reported in pre-- and post--menopausal women [31,41], however our results suggest PPARG variation is not a major player in the regulation of bone strength, which may reflect ethnic differences between Japanese and Swedish populations as well as the analysis of different SNPs.…”

Section: Discussioncontrasting

confidence: 63%

“…For ALOX15, with the exception of rs8074545 upstream of the coding region (which is intergenic and therefore has potential functionality) all selected SNPs were tagging SNPs previously investigated for BMD (rs748694; rs9894225; rs916055; rs2619112) [20]. The IL--6 tagging SNP rs10242595, located downstream of the coding region was selected for its previous association with decreased fat mass [40] while PPARγ rs1801282 (Pro12Ala) is the most extensively examined in a variety of diseases including osteoporosis [31].…”

Section: Genotypingmentioning

confidence: 99%

Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly

Herlin

McGuigan

Luthman

et al. 2015

Bone

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“…The total genomic DNA was isolated by a standard procedure 13. The genotypes of the PPARG2 Pro12Ala missense mutation were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using primers and conditions described previously 1415. PCR reactions were performed with 10 pmol each of sense primer (5’-GCCAATTCAAGCCCAGTC-3’) and an antisense (primer 5’-GATATGTTTGCAGACAGTGT ATCAGTGAAGGAATCGCTTTCCG-3’) that flank the region containing the 12-amino acid site of PPARG2 16.…”

Section: Methodsmentioning

confidence: 99%

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

Al-Jarallah

Shehab

Haider

2011

Annals of Saudi Medicine

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BACKGROUND AND OBJECTIVES:Peroxisome proliferator–activated receptors (PPARs) play an important role in a number of cellular and metabolic functions. This study was carried out to determine the prevalence of a missense mutation (Pro12Ala) in the PPARG2 gene in Kuwaiti Arab patients with primary knee osteoarthritis (OA) and healthy controls with the aim of identifying a possible association.DESIGN AND SETTING:A prospective cross-sectional study carried out at three major teaching hospitals (referral centers) in the country over a one-year period.PATIENTS AND METHODS:The prevalence of PPARG2 gene Pro12Ala missense mutation was determined in 104 Kuwaiti Arab patients with primary knee OA and 111 ethnically matched healthy controls. The prevalence of this Pro12Ala missense mutation was also determined in clinical subgroups of OA patients divided on the basis of age at onset, function and radiologic grading.RESULTSThe Pro-Pro genotype of the PPARG2 gene Pro12Ala missense mutation was detected in 95/104 (91.3%) cases compared to 111/111 (100%) in the control subjects. The heterozygous Pro-Ala genotype was detected in 9/104 (8.7%) of the OA patients, while it was not detected in any of the controls. The Ala-Ala genotype was not detected in any of the OA patients or the controls. No significant differences were detected in the PPARG2 gene Pro12Ala genotypes in the subgroups of patients classified on the basis of age at onset, functional assessment using Lequesne’s functional index, and radiological grading using Kellgren-Lawrence (K-L) grading.CONCLUSIONSThis study found no significant association between the PPARG2 gene Pro12Ala missense mutation and knee OA. However, the presence of the Pro-Pro genotype of the PPARG2 gene mutation has a protective effect against development of OA.

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Association of Bone Mineral Density with a Polymorphism of the Peroxisome Proliferator-Activated Receptor γ Gene: PPARγ Expression in Osteoblasts

Cited by 101 publications

References 36 publications

The Insulin-like Growth Factor-1 Binding Protein Acid-labile Subunit Alters Mesenchymal Stromal Cell Fate

The Insulin-like Growth Factor-1 Binding Protein Acid-labile Subunit Alters Mesenchymal Stromal Cell Fate

Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly

Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis

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