Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

Cho, Sun Wook; Yang, Jae Yeon; Her, Sun Ju; Choi, Hyo Geun; Jung, Ju Yeon; Sun, Hyun Jin; An, Jee Hyun; Cho, Hwa Young; Kim, Sang Wan; Park, Kyong Soo; Kim, Seong Yeon; Baek, Woon Yi; Kim, Jung Eun; Yim, Mijung; Shin, Chan Soo

doi:10.1002/jbmr.366

Cited by 46 publications

(51 citation statements)

References 66 publications

(77 reference statements)

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“…For example, female rats treated with rosiglitazone did not exhibit any adverse effect on bone, while ovariectomy in these rats led to a significant rosiglitazone-induced bone loss, indicating that TZDs may enhance the bone loss induced by estrogen deprivation (Sottile et al 2004). This is in agreement with a recent study in transgenic mice overexpressing PPARg in osteoblasts, in which the bone loss in female became evident only after ovariectomy, although the male mice also exhibited reduced bone mass (Cho et al 2011). Clinical studies have also shown that TZDs have greater effects on bone loss (Berberoglu et al 2010) and risk of fractures (Kahn et al 2008) in postmenopausal women with type 2 diabetes than in males.…”

Section: Ampk and The Skeletal Effects Of Antidiabetic Drugssupporting

confidence: 90%

AMP-activated protein kinase pathway and bone metabolism

Jeyabalan

Shah²,

Viollet³

et al. 2011

Journal of Endocrinology

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There is increasing evidence that osteoporosis, similarly to obesity and diabetes, could be another disorder of energy metabolism. AMP-activated protein kinase (AMPK) has emerged over the last decade as a key sensing mechanism in the regulation of cellular energy homeostasis and is an essential mediator of the central and peripheral effects of many hormones on the metabolism of appetite, fat and glucose. Novel work demonstrates that the AMPK signaling pathway also plays a role in bone physiology. Activation of AMPK promotes bone formation in vitro and the deletion of a or b subunit of AMPK decreases bone mass in mice. Furthermore, AMPK activity in bone cells is regulated by the same hormones that regulate food intake and energy expenditure through AMPK activation in the brain and peripheral tissues. AMPK is also activated by antidiabetic drugs such as metformin and thiazolidinediones (TZDs), which also impact on skeletal metabolism. Interestingly, TZDs have detrimental skeletal side effects, causing bone loss and increasing the risk of fractures, although the role of AMPK mediation is still unclear. These data are presented in this review that also discusses the potential roles of AMPK in bone as well as the possibility for AMPK to be a future therapeutic target for intervention in osteoporosis.

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Section: Ampk and The Skeletal Effects Of Antidiabetic Drugssupporting

confidence: 90%

AMP-activated protein kinase pathway and bone metabolism

Jeyabalan

Shah²,

Viollet³

et al. 2011

Journal of Endocrinology

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“…Following OVX at 4 months old, C57BL/6J prostaglandin E2 receptor (one of the four prostanoid receptors) knockout mice exhibited protection against bone loss in femur and L4 vertebrae (31). However, when OVX was performed on 30-week-old female Col.1-PPARγ mice, ovariectomy-induced bone loss was accelerated (10). As the present results revealed that the factor age of C57BL/6J influenced the sensitivity of bone to OVX, the conclusions of a specific gene on osteoporosis must be identified with care.…”

Section: -Week-old ------------------------------------------------mentioning

confidence: 99%

“…However, compared with rats, mice may be a more effective model as they have a more easily manipulated genome and lower drug doses are required for treatment. Several strains of mice have been used in postmenopausal osteoporosis research (10)(11)(12)(13). However, there are controversies regarding the use of C57BL/6J mice as an animal model for postmenopausal osteoporosis (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

“…However, there are controversies regarding the use of C57BL/6J mice as an animal model for postmenopausal osteoporosis (14)(15)(16). The starting age of C57BL/6J mice subjected to ovariectomy varies from 4 to 30 weeks old (10,(15)(16)(17)(18). Certain combinations of age, skeletal site and time post-surgery may lead to varying levels of bone alterations in response to estrogen deficiency in female rats (6).…”

Section: Introductionmentioning

confidence: 99%

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Age-dependent variations of cancellous bone in response to ovariectomy in C57BL/6J mice

et al. 2018

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Abstract. The ovariectomized (OVX) mouse model has been widely accepted to be suitable for the study of postmenopausal osteoporosis. However, whether C57BL/6J mice, a commonly used genetic background mouse strain, is an appropriate model for postmenopausal osteoporosis remains controversial. The present study investigated the effect of the OVX model on alterations in bone density and microarchitecture in C57BL/6J female mice of different ages. C57BL/6J mice were divided into 8-, 12-and 16-week-old groups (OVX 8 , OVX 12 and OVX 16 ) from the beginning of OVX. At 8 weeks post-surgery, the mice were anesthetized and micro-computed tomography was used to analyze the bone density and microarchitecture. The results revealed that OVX-induced loss of cancellous bone was greatest in OVX 8 , moderate in OVX 12 , and only a weak bone loss was observed in the OVX 16 group when compared with the SHAM 16 control group. In addition, the effect of genetic backgrounds in response to the OVX model were examined. Several other strains of mice, including inbred (BALB/c) and outbred (ICR and Kunming), were used in the present study, all of which were subjected to OVX at 8 weeks of age. The present findings revealed that the highest rate of bone loss was detected in C57BL/6J female mice. In addition, treatment with estrogen (17β-estradiol, 30 µg/kg five times per week) led to a significant increase in bone density in C57BL/6J mice compared with the other strains of mice. Therefore, these results may provide novel insights into the age-and strain-associated effect of OVX on regulating turnover of bone in female mice. The present findings also suggest 8-week-old C57BL/6J mice as an animal model for postmenopausal osteoporosis and preclinical testing of potential therapies for this disease.

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“…39 Briefly, total BM cells from femora and tibiae were flushed out using a 27-gauge needle, and the resulting cells were cultured in an a-MEM supplemented with 10% FBS, 1% glutamine, and 30 ng/mL macrophage colony-stimulating factor (M-CSF) for 3 days. To induce osteoclast formation, BMMs were treated with M-CSF (30 ng/mL) and receptor activator of nuclear factor kappa-B ligand (RANKL; 50 ng/ mL) in the presence or absence of 0.5· or 1· hUCB-MSC CM in 96-well culture plates (Corning LifeSciences, Edison, NJ).…”

Section: In Vitro Effect Of Hucb-msc CM On Osteoclastic Differentiationmentioning

confidence: 99%

Transplantation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells or Their Conditioned Medium Prevents Bone Loss in Ovariectomized Nude Mice

Park

Song

et al. 2013

Tissue Engineering Part A

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Umbilical cord blood (UCB) has recently been recognized as a new source of mesenchymal stem cells (MSCs) for use in stem cell therapy. We studied the effects of systemic injection of human UCB-MSCs and their conditioned medium (CM) on ovariectomy (OVX)-induced bone loss in nude mice. Ten-week-old female nude mice were divided into six groups: Sham-operated mice treated with vehicle (Sham-Vehicle), OVX mice subjected to UCBMSCs (OVX-MSC), or human dermal fibroblast (OVX-DFB) transplantation, OVX mice treated with UCB-MSC CM (OVX-CM), zoledronate (OVX-Zol), or vehicle (OVX-Vehicle). Although the OVX-Vehicle group exhibited significantly less bone mineral density (BMD) gain compared with the Sham-Vehicle group, transplantation of hUCB-MSCs (OVX-MSC group) has effectively prevented OVX-induced bone mass attenuation. Notably, the OVX-CM group also showed BMD preservation comparable to the OVX-MSC group. In addition, microcomputed tomography analysis demonstrated improved trabecular parameters in both the OVX-MSC and OVX-CM groups compared to the OVX-Vehicle or OVX-DFB group. Histomorphometric analysis showed increased bone formation parameters, accompanied by increased serum procollagen type-I N-telopeptide levels in OVX-MSC and OVX-CM mice. However, cell-trafficking analysis failed to demonstrate engraftment of MSCs in bone tissue 48 h after cell infusion. In vitro, hUCB-MSC CM increased alkaline phosphatase (ALP) activity in human bone marrow-derived MSCs and mRNA expression of collagen type 1, Runx2, osterix, and ALP in C3H10T1/2 cells. Furthermore, hUCB-MSC CM significantly increased survival of osteocyte-like MLO-Y4 cells, while it inhibited osteoclastic differentiation. To summarize, transplantation of hUCB-MSCs could effectively prevent OVX-mediated bone loss in nude mice, which appears to be mediated by a paracrine mechanism rather than direct engraftment of the MSCs.

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Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

Cited by 46 publications

References 66 publications

AMP-activated protein kinase pathway and bone metabolism

AMP-activated protein kinase pathway and bone metabolism

Age-dependent variations of cancellous bone in response to ovariectomy in C57BL/6J mice

Transplantation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells or Their Conditioned Medium Prevents Bone Loss in Ovariectomized Nude Mice

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