Neuropeptide Y mediates glucocorticoid-induced osteoporosis and marrow adiposity in mice

Wang, F.-S.; Lian, Wei; Weng, Wen-Tsan; Sun, Yan; Ke, Huei-Ching; Chen, Y.-S.; Ko, Jih‐Yang

doi:10.1007/s00198-016-3598-3

Cited by 25 publications

(19 citation statements)

References 45 publications

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“…For example, therapies involving intermittent PTH, (22,24) sost-antibody, (18) anti-Rankl antibody, (19) IL-6 neutralizing antibody, (25) as well as inhibition of HSP90 (26) and endoplasmic reticulum stress (23) prevented the bone phenotypes due to GC treatment to variable degrees in vivo. Moreover, genetic approaches using knockout mice of mitogen-activated protein kinase phosphatase 1, (27) plasminogen activator inhibitor 1, (28) Npy, (29) sost, (14) and autophagy-related gene 7 (30) have been used to prevent GC-induced bone loss but resulted in variable outcomes. Our transgenic (TG) mice that overexpress human WNT16 in bone tissue displayed significantly higher bone mineral density in whole body, hip, and spine.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of WNT16 Does Not Prevent Cortical Bone Loss Due to Glucocorticoid Treatment in Mice

et al. 2018

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Glucocorticoids (GC) are commonly used for the treatment of a wide variety of autoimmune, pulmonary, gastrointestinal, and malignancy conditions. One of the devastating side effects of GC use is osteoporotic fractures, particularly in the spine and hip. Bisphosphonates (BP) are the most commonly prescribed pharmacological agents for the prevention and treatment of GC‐induced osteoporosis (GIO). However, GIO is marked by reduced bone formation and BP serves mainly to decrease bone resorption. The WNT signaling pathway plays a major role in bone and mineral homeostasis. Previously, we demonstrated that overexpression of WNT16 in mice led to higher bone mineral density and improved bone microarchitecture and strength. We hypothesized that WNT16 overexpression would prevent bone loss due to glucocorticoid treatment in mice. To test our hypothesis, we treated adult wild‐type and WNT16‐transgenic mice with vehicle and GC (prednisolone; 2.1 mg/kg body weight) via slow‐release pellets for 28 days. We measured bone mass and microarchitecture by dual‐energy X‐ray absorptiometry (DXA) and micro‐CT, and performed gene expression and serum biochemical analysis. We found that GC treatment compared with the vehicle significantly decreased femoral areal bone mineral density (aBMD), bone mineral content (BMC), and cortical bone area and thickness in both wild‐type and transgenic female mice. In contrast, the trabecular bone parameters at distal femur were not significantly changed by GC treatment in male and female mice for both genotypes. Further, we observed significantly lower level of serum P1NP and a tendency of higher level of serum TRAP in wild‐type and transgenic mice due to GC treatment in both sexes. Gene expression analysis showed lower mRNA levels of Wnt16 , Opg , and Opg/Rankl ratio in GC‐treated female mice for both genotypes compared with the sex‐matched vehicle‐treated mice. These data suggest that although WNT16 overexpression resulted in higher baseline bone mineral density and bone volume per trabecular volume (BV/TV) in the transgenic mice, this was insufficient to prevent bone loss in mice due to glucocorticoid treatment. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Overexpression of WNT16 Does Not Prevent Cortical Bone Loss Due to Glucocorticoid Treatment in Mice

et al. 2018

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“…Excessive use of glucocorticoids damaged the function of bone cells [4,6], and the NPY system was found to play a negative role in the regulation of bone remodeling and osteoblast activity [9,12,17,25]. A recent study has suggested that NPY signaling mediated glucocorticoid-induced osteoporosis in mice [20]. The Y1 receptor, one of the most important receptors for NPY, was expressed in osteoblasts and participated in the regulation of bone metabolism [11,12].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a recent study demonstrated that increased NPY expression was associated with glucocorticoid-induced bone loss and marrow adiposity in mice, whereas NPY deletion protected bone tissue against glucocorticoid-induced deterioration [20]. The Y1 receptor is the main receptor for NPY; however, its role in the glucocorticoid-induced suppression of osteoblast differentiation at the cell level has not yet been defined.…”

Section: Introductionmentioning

confidence: 99%

Neuropeptide Y1 Receptor Regulates Glucocorticoid-Induced Inhibition of Osteoblast Differentiation in Murine MC3T3-E1 Cells via ERK Signaling

Zhu

et al. 2016

IJMS

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High dose glucocorticoid (GC) administration impairs the viability and function of osteoblasts, thus causing osteoporosis and osteonecrosis. Neuropeptide Y1 receptor (Y1 receptor) is expressed in bone tissues and cells, and regulates bone remodeling. However, the role of Y1 receptor in glucocorticoid-induced inhibition of osteoblast differentiation remains unknown. In the present study, osteoblastic cell line MC3T3-E1 cultured in osteogenic differentiation medium was treated with or without of 10−7 M dexamethasone (Dex), Y1 receptor shRNA interference, Y1 receptor agonist [Leu31, Pro34]-NPY, and antagonist BIBP3226. Cell proliferation and apoptosis were assessed by cell counting kit-8 (CCK-8) assay and cleaved caspase expression, respectively. Osteoblast differentiation was evaluated by Alizarin Red S staining and osteogenic marker gene expressions. Protein expression was detected by Western blot analysis. Dex upregulated the expression of Y1 receptor in MC3T3-E1 cells associated with reduced osteogenic gene expressions and mineralization. Blockade of Y1 receptor by shRNA transfection and BIBP3226 significantly attenuated the inhibitory effects of Dex on osteoblastic activity. Y1 receptor signaling modulated the activation of extracellular signal-regulated kinases (ERK) as well as the expressions of osteogenic genes. Y1 receptor agonist inhibited ERK phosphorylation and osteoblast differentiation, while Y1 receptor blockade exhibited the opposite effects. Activation of ERK signaling by constitutive active mutant of MEK1 (caMEK) abolished Y1 receptor-mediated Dex inhibition of osteoblast differentiation in MC3T3-E1 cells. Taken together, Y1 receptor regulates Dex-induced inhibition of osteoblast differentiation in murine MC3T3-E1 cells via ERK signaling. This study provides a novel role of Y1 receptor in the process of GC-induced suppression in osteoblast survival and differentiation.

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“…GC are known to inhibit bone formation and high levels of GC in human (Cushing syndrome) are associated with increased risk of fractures and increased MAT formation. GC stimulates the synthesis of collagenase III, which is an enzyme involved in bone matrix degradation, inhibits the anabolic effect of IGF hormones and induces significant changes in neuropeptide Y that may contribute to osteoporosis and increased MAT phenotype (76). Life-course timepoint analysis has shown that circulating GC follow an age-related trajectory, which can be affected by both the external environment and internal physiological events, which varies between gender and individuals (77).…”

Section: Glucocorticoids (Gc)mentioning

confidence: 99%

Aging and lineage allocation changes of bone marrow skeletal (stromal) stem cells

Nehlin

Jafari

Tencerová

et al. 2019

Bone

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Aging is associated with decreased bone mass and accumulation of bone marrow adipocytes. Both bone forming osteoblastic cells and bone marrow adipocytes are derived from a stem cell population within the bone marrow stroma called bone marrow stromal (skeletal or mesenchymal) stem cells (BMSC). In the present review, we provide an overview, based on the current literature, regarding the physiological aging processes that cause changes in BMSC lineage allocation, enhancement of adipocyte and defective osteoblast differentiation, leading to gradual exhaustion of stem cell regenerative potential and defects in bone tissue homeostasis and metabolism. We discuss strategies to preserve the "youthful" state of BMSC, to reduce bone marrow age-associated adiposity, and to counteract the overall negative effects of aging on bone tissues with the aim of decreasing bone fragility and risk of fractures.

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Neuropeptide Y mediates glucocorticoid-induced osteoporosis and marrow adiposity in mice

Cited by 25 publications

References 45 publications

Overexpression of WNT16 Does Not Prevent Cortical Bone Loss Due to Glucocorticoid Treatment in Mice

Overexpression of WNT16 Does Not Prevent Cortical Bone Loss Due to Glucocorticoid Treatment in Mice

Neuropeptide Y1 Receptor Regulates Glucocorticoid-Induced Inhibition of Osteoblast Differentiation in Murine MC3T3-E1 Cells via ERK Signaling

Aging and lineage allocation changes of bone marrow skeletal (stromal) stem cells

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