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Wenjing Wu Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Jiayao Fu Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Yijing Gu Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Yu Wei Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Pengfei Ma Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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Junhua Wu Department of Prosthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China

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vitro and in vivo . We also investigated the role of the JAK2/STAT3 signalling pathway in the inflammation-senescence-SASP feedback loop. Our findings provided a potential new target for preventing postmenopausal osteoporosis. Materials and

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Kenichi Serizawa Product Research Department, Product Research Department, Medical Science Department, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

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Kenji Yogo Product Research Department, Product Research Department, Medical Science Department, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

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Yoshihito Tashiro Product Research Department, Product Research Department, Medical Science Department, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

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Satoshi Takeda Product Research Department, Product Research Department, Medical Science Department, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

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Ryohei Kawasaki Product Research Department, Product Research Department, Medical Science Department, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

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Ken Aizawa Product Research Department, Product Research Department, Medical Science Department, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

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Koichi Endo Product Research Department, Product Research Department, Medical Science Department, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

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-specific regulation of PPARγ. Limitations of this study OVX model is the most commonly used and extensively studied animal model of postmenopausal osteoporosis. FDA guidelines state that OVX rat model is appropriate for evaluation of agents to prevent bone loss in

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Lingyun Lu Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

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Li Tian Laboratory of Endocrinology and Metabolism, Department of Endocrinology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

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bone absorption, causing substantial bone loss ( Raehtz et al. 2017 , Li & Wang 2018 ). These changes are the pathogenesis of postmenopausal osteoporosis. According to the published data, one-third of women over 50 years of age will experience

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Y Kudo
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M Iwashita
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S Itatsu
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T Iguchi
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Y Takeda
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Abstract

The cellular mechanisms involved in the accelerated bone loss occurring in association with estrogen deprivation as seen following the menopause are not fully understood. Insulin-like growth factor-I (IGF-I) is the local regulator of osteoblasts and one of its binding proteins, insulin-like growth factor-binding protein-4 (IGFBP-4), binds to IGF-I and suppresses biological activity. Previous studies have shown that the binding activity of IGFBP-4 in the conditioned medium of parathyroid hormone (PTH)-treated SaOS-2 osteoblastic-like cells is enhanced twofold and that this PTH-enhanced IGFBP-4 binding activity is abolished by 17β-estradiol. Levels of IGFBP-4 in the conditioned medium have been reported to be regulated not only at the level of production but also at the level of degradation which is catalyzed by a protease that specifically cleaves IGFBP-4. We have, therefore, studied the effects of 17β-estradiol and PTH on IGFBP-4 protease activity using SaOS-2 cells. SaOS-2 cells produce a protease that specifically cleaves IGFBP-4 into two fragments of approximately 18 and 14 kilodaltons. IGFBP-4 protease activity in the conditioned medium from PTH-treated cells was suppressed, while this PTH-induced suppression of protease activity was reversed by the addition of 17β-estradiol to the cultures. IGFBP-4 proteolytic activity was stimulated by IGF-I or IGF-II added exogenously and was inhibited by EDTA or protease inhibitors. IGFBP-4 proteolyzed in the conditioned medium from cells treated with PTH and 17β-estradiol was less effective at inhibiting IGF-I-stimulated [3H]thymidine incorporation into DNA compared with that proteolyzed in the conditioned medium from PTH-treated cells. The simplest explanation is that 17β-estradiol suppressed the inhibitory effect of PTH on osteoblastic activity by inhibiting the PTH-induced suppression of IGFBP-4 protease activity.

Journal of Endocrinology (1996) 150, 223–229

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Wang Xiao Departments of Orthopaedics, Gynaecology, Department of Orthopaedic Research Institution, Department of Medicine, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, 215004 Suzhou, China

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Fei Beibei Departments of Orthopaedics, Gynaecology, Department of Orthopaedic Research Institution, Department of Medicine, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, 215004 Suzhou, China

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Shen Guangsi Departments of Orthopaedics, Gynaecology, Department of Orthopaedic Research Institution, Department of Medicine, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, 215004 Suzhou, China

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Jiang Yu Departments of Orthopaedics, Gynaecology, Department of Orthopaedic Research Institution, Department of Medicine, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, 215004 Suzhou, China

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Zhang Wen Departments of Orthopaedics, Gynaecology, Department of Orthopaedic Research Institution, Department of Medicine, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, 215004 Suzhou, China

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Huang Xi Departments of Orthopaedics, Gynaecology, Department of Orthopaedic Research Institution, Department of Medicine, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, 215004 Suzhou, China

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Xu Youjia Departments of Orthopaedics, Gynaecology, Department of Orthopaedic Research Institution, Department of Medicine, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, 215004 Suzhou, China

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Introduction Primary type I osteoporosis, also known as postmenopausal osteoporosis (PMO), is a bone disease associated with reduced bone mineral density, disordered bone architecture and increased fragility ( Chinese Orthopaedic Association 2009

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Sonu Khanka Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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Charul Somani Department of Chemistry, Mohanlal Sukhadia University, Udaipur-Rajasthan, India

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Kriti Sharma Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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Shivani Sharma Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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Akhilesh Kumar Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
Sophisticated Analytical Instrument Facility & Research, Division, CSIR-Central Drug Research Institute, Lucknow, India

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Naibedya Chattopadhyay Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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Sanjeev K Kanojiya Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
Sophisticated Analytical Instrument Facility & Research, Division, CSIR-Central Drug Research Institute, Lucknow, India

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Dinesh Kumar Yadav Department of Chemistry, Mohanlal Sukhadia University, Udaipur-Rajasthan, India

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Divya Singh Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

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considered a main factor for postmenopausal osteoporosis pathogenesis ( Okman-Kilic 2015 ), it made hormonal replacement treatment popular for the prevention of bone loss in postmenopausal women. However, estrogen therapy has well-known adverse effects like

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S Ö Íşeri Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
School of Pharmacy, Department of Pharmacology, Marmara University School of Medicine, Istanbul, Turkey
Department of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
Vocational School of Health Related Professions, Marmara University School of Medicine, Istanbul, Turkey
Division of Biochemistry, Kasimpasa Military Hospital, Istanbul, Turkey

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G Şener Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
School of Pharmacy, Department of Pharmacology, Marmara University School of Medicine, Istanbul, Turkey
Department of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
Vocational School of Health Related Professions, Marmara University School of Medicine, Istanbul, Turkey
Division of Biochemistry, Kasimpasa Military Hospital, Istanbul, Turkey

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M Yüksel Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
School of Pharmacy, Department of Pharmacology, Marmara University School of Medicine, Istanbul, Turkey
Department of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
Vocational School of Health Related Professions, Marmara University School of Medicine, Istanbul, Turkey
Division of Biochemistry, Kasimpasa Military Hospital, Istanbul, Turkey

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G Contuk Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
School of Pharmacy, Department of Pharmacology, Marmara University School of Medicine, Istanbul, Turkey
Department of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
Vocational School of Health Related Professions, Marmara University School of Medicine, Istanbul, Turkey
Division of Biochemistry, Kasimpasa Military Hospital, Istanbul, Turkey

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Ş Çetinel Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
School of Pharmacy, Department of Pharmacology, Marmara University School of Medicine, Istanbul, Turkey
Department of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
Vocational School of Health Related Professions, Marmara University School of Medicine, Istanbul, Turkey
Division of Biochemistry, Kasimpasa Military Hospital, Istanbul, Turkey

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N Gedik Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
School of Pharmacy, Department of Pharmacology, Marmara University School of Medicine, Istanbul, Turkey
Department of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
Vocational School of Health Related Professions, Marmara University School of Medicine, Istanbul, Turkey
Division of Biochemistry, Kasimpasa Military Hospital, Istanbul, Turkey

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B Ç Yeğen Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
School of Pharmacy, Department of Pharmacology, Marmara University School of Medicine, Istanbul, Turkey
Department of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
Vocational School of Health Related Professions, Marmara University School of Medicine, Istanbul, Turkey
Division of Biochemistry, Kasimpasa Military Hospital, Istanbul, Turkey

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bone resorption, including postmenopausal osteoporosis, Paget’s disease, hypercalcemia of malignancy and osteolytic bone metastases ( Fleisch 1997 , Meunier et al. 1999 ). These agents are analogs of pyrophosphate, an endogenous inhibitor of bone

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S Boonen
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J Aerssens
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J Dequeker
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Introduction

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (Peck et al. 1993). Type I (postmenopausal) osteoporosis is characterized by a disproportionate postmenopausal trabecular bone loss in a subset of women and complicated by vertebral compression fractures. Type II (senile) osteoporosis, on the other hand, is associated with a proportionate age-related loss of both cortical and trabecular bone, in men as well as in women, ultimately leading to hip fractures (Riggs & Melton 1983). Fractures of the proximal femur in the elderly represent a global issue, associated with significant morbidity and mortality (Cummings et al. 1985, Maggi et al. 1991, Mander & Lindahl 1993, Melton 1993). The cumulative incidence of hip fractures reaches 33% in women and 17% in men by 90 years of age (Melton et al. 1992). However

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KC Lee
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H Jessop
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R Suswillo
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G Zaman
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LE Lanyon
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Postmenopausal osteoporosis represents a failure of the response by which bone cells adapt bone mass and architecture to be sufficiently strong to withstand loading without fracture. To address why this failure should be associated with oestrogen withdrawal, we investigated the ulna's adaptive response to mechanical loading in adult female mice lacking oestrogen receptor-alpha (ERalpha(-/-)), those lacking oestrogen receptor-beta (ERbeta(-/-)) and their wild-type littermates. In wild-type mice, short periods of physiologic cyclic compressive loading of the ulna in vivo over a 2-week period stimulates new bone formation. In ERalpha(-/-) and ERbeta(-/-) mice this osteogenic response was respectively threefold and twofold less (P<0.05). In vitro, primary cultures of osteoblast-like cells derived from these mice were subjected to a single short period of mechanical strain. Twenty-four hours after strain the number of wild-type cells was 61+/-25% higher than in unstrained controls (P<0.05), whereas in ERalpha(-/-) cells there was no strain-related increase in cell number. However, the strain-related response of ERalpha(-/-) cells could be partially rescued by transfection with functional human ERalpha (P<0.05). ERbeta(-/-) cells showed a 125+/-40% increase in cell number following strain. This was significantly greater than in wild types (P<0.05).These data support previous findings that functional ERalpha is required for the full osteogenic response to mechanical loading and particularly the stage of this response, which involves an increase in osteoblast number. ERbeta appears to depress the ERalpha-mediated strain-related increase in osteoblast number in vitro, but in female transgenic mice in vivo the constitutive absence of either ERalpha or ERbeta appears to diminish the osteogenic response to loading.

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