DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide

Zhang, Ying; Chen, Guang‐Pei; Gu, Zhifeng; Sun, Hai-Jian; Karaplis, Andrew C.; Goltzman, David; Miao, Dengshun

doi:10.7150/ijbs.23318

Cited by 15 publications

(10 citation statements)

References 27 publications

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“…Immunohistochemical staining was carried out as described previously 40 for β-galactosidase (β-gal), P16 INK4a , using the avidin-biotin-peroxidase complex technique with affinity-purified rabbit anti-mouse β-gal (Santa Cruz, CA, USA), P16 INK4a (Santa 192Cruz, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Pyrroloquinoline Quinone Prevents Estrogen Deficiency-Induced Osteoporosis by Inhibiting Oxidative Stress and Osteocyte Senescence

et al. 2019

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Accumulating studies have shown that oxidative stress increases with aging, which is related to the pathophysiology of postmenopausal osteoporosis. Pyrroloquinoline quinone (PQQ) is a natural anti-oxidant with anti-oxidative and anti-aging effects. However, it is unclear whether PQQ has a protective role against estrogen deficiency-induced osteoporosis. Here, we evaluated the efficacy of PQQ on bone mineral density, bone microarchitecture, bone turnover and biomechanical strength in ovariectomy (OVX)-induced osteoporosis mouse model. Although dietary PQQ supplement did not affect serum E2 levels and uterine weight in OVX mice, it could prevent OVX-induced bone loss and improve bone strength by inhibiting oxidative stress, osteocyte senescence and senescence-associated secretory phenotype (SASP), subsequently promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption, which was comparable to treatment with exogenous estrogen. The results from our study provide experimental evidence for the clinical use of PQQ to prevent estrogen deficiency-induced osteoporosis.

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Section: Methodsmentioning

confidence: 99%

Pyrroloquinoline Quinone Prevents Estrogen Deficiency-Induced Osteoporosis by Inhibiting Oxidative Stress and Osteocyte Senescence

et al. 2019

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“…Tibiae were removed and histologically processed as described previously . The paraffin sections were stained with hematoxylin and eosin, histochemically for total collagen and ALP activity, immunohistochemically for type I collagen as described .…”

Section: Methodsmentioning

confidence: 99%

“…Membrane was blotted with primary antibodies against SOD1 (Abcam, MA), p16 (Santa Cruz, MA), p19 (Cell Signaling Technology, Danvers, MA), and β‐actin (Bioworld Technology, St. Louis Park, MN) were used as loading control. Immunoblotting was carried out as we described previously .…”

Section: Methodsmentioning

confidence: 99%

Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress

Chen

Zhang

et al. 2019

Stem Cells

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We previously demonstrated that Bmi1 deficiency leads to osteoporosis phenotype by inhibiting the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs), but it is unclear whether overexpression of Bmi1 in MSCs stimulates skeletal development and rescues Bmi1 deficiency‐induced osteoporosis. To answer this question, we constructed transgenic mice (Bmi1Tg) that overexpressed Bmi1 driven by the Prx1 gene and analyzed their skeletal phenotype differences with that of wild‐type littermates. We then hybridized Bmi1Tg to Bmi1−/− mice to generate Bmi1−/− mice overexpressing Bmi1 in MSCs and compared their skeletal phenotypes with those of Bmi1−/− and wild‐type mice using imaging, histopathological, immunohistochemical, histomorphometric, cellular, and molecular methods. Bmi1Tg mice exhibited enhanced bone growth and osteoblast formation, including the augmentation of bone size, cortical and trabecular volume, number of osteoblasts, alkaline phosphatase (ALP)‐positive and type I collagen‐positive areas, number of total colony forming unit fibroblasts (CFU‐f) and ALP+ CFU‐f, and osteogenic gene expression levels. Consistently, MSC overexpressing Bmi1 in the Bmi1−/− background not only largely reversed Bmi1 systemic deficiency‐induced skeletal growth retardation and osteoporosis, but also partially reversed Bmi1 deficiency‐induced systemic growth retardation and premature aging. To further explore the mechanism of action of MSCs overexpressing Bmi1 in antiosteoporosis and antiaging, we examined changes in oxidative stress and expression levels of p16 and p19. Our results showed that overexpression of Bmi1 in MSCs inhibited oxidative stress and downregulated p16 and p19. Taken together, the results of this study indicate that overexpression of Bmi1 in MSCs exerts antiaging and antiosteoporosis effects by inactivating p16/p19 signaling and inhibiting oxidative stress. stem cells 2019;37:1200–1211

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“…A series of studies [157][158][159] have demonstrated that mice that express only a nuclear localization signal (NLS)-deficient form of parathyroid hormone-related protein (PTHrP) have growth retardation and an accelerated ageing phenotype in multiple tissues, which is characterized by increased cellular senescence in multiple tissues. Loss of the PTHrP NLS results in reduced expression of Bmi1, a member of the Polycomb-Trithorax gene family that regulates gene expression through chromatin remodelling 157 .…”

Section: Parathyroid Hormone-related Protein and Regulation Of The Grmentioning

confidence: 99%

The role of cellular senescence in ageing and endocrine disease

et al. 2020

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With the ageing of the global population, interest is growing in the 'geroscience hypothesis', which posits that manipulation of fundamental ageing mechanisms will delay (in parallel) the appearance or severity of multiple chronic, non-communicable diseases, as these diseases share the same underlying risk factor-namely, ageing. In this context, cellular senescence has received considerable attention as a potential target in preventing or treating multiple age-related diseases and increasing healthspan. Here we review mechanisms of cellular senescence and approaches to target this pathway therapeutically using 'senolytic' drugs that kill senescent cells or inhibitors of the senescence-associated secretory phenotype (SASP). Furthermore, we highlight the evidence that cellular senescence has a causative role in multiple diseases associated with ageing. Finally, we focus on the role of cellular senescence in a number of endocrine diseases, including osteoporosis, metabolic syndrome and type 2 diabetes mellitus, as well as other endocrine conditions. Although much remains to be done, considerable preclinical evidence is now leading to the initiation of proof-of-concept clinical trials using senolytics for several endocrine and nonendocrine diseases. Ageing is now generally accepted as the single largest risk factor for many of the major chronic diseases (for example, type 2 diabetes mellitus (T2DM), cardiovascular disease and cancer) that account for the bulk of morbidity, deaths and health costs in the USA and other developed countries 1. For these conditions, the predictive ability of advanced chronological age exceeds the predictive ability of all other risk factors combined. Enormous progress has been made over the years in the development of specific drugs to treat individual diseases associated with ageing, including metabolic dysfunction and T2DM (for example, GLP1R agonists and DPP4 inhibitors), skeletal fragility and osteoporosis (for example,

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DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide

Cited by 15 publications

References 27 publications

Pyrroloquinoline Quinone Prevents Estrogen Deficiency-Induced Osteoporosis by Inhibiting Oxidative Stress and Osteocyte Senescence

Pyrroloquinoline Quinone Prevents Estrogen Deficiency-Induced Osteoporosis by Inhibiting Oxidative Stress and Osteocyte Senescence

Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress

The role of cellular senescence in ageing and endocrine disease

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