Browsing by Subject "bone resorption"

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    Inhibiting checkpoint kinase 1 protects bone from bone resorption by mammary tumor in a mouse model
    (Impact Journals, 2018-01-19) Liu, Shengzhi; Liu, Yang; Minami, Kazumasa; Chen, Andy; Wan, Qiaoqiao; Yin, Yukun; Gan, Liangying; Xu, Aihua; Matsuura, Nariaki; Koizumi, Masahiko; Liu, Yunlong; Na, Sungsoo; Li, Jiliang; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
    DNA damage response plays a critical role in tumor growth, but little is known about its potential role in bone metabolism. We employed selective inhibitors of Chk1 and examined their effects on the proliferation and migration of mammary tumor cells as well as the development of osteoblasts and osteoclasts. Further, using a mouse model of bone metastasis we evaluated the effects of Chk1 inhibitors on bone quality. Chk1 inhibitors blocked the proliferation, survival, and migration of tumor cells in vitro and suppressed the development of bone-resorbing osteoclasts by downregulating NFATc1. In the mouse model, Chk1 inhibitor reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Analysis of RNA-seq expression data indicated that the observed effects were mediated through the regulation of eukaryotic translation initiation factor 2 alpha, stress to the endoplasmic reticulum, S100 proteins, and bone remodeling-linked genes. Our findings suggest that targeting Chk1 signaling without adding DNA damaging agents may protect bone from degradation while suppressing tumor growth and migration.
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    Role and mechanism of action of Sclerostin in bone
    (Elsevier, 2017-03) Delgado-Calle, Jesus; Sato, Amy Y.; Bellido, Teresita; Anatomy and Cell Biology, School of Medicine
    After discovering that lack of Sost/sclerostin expression is the cause of the high bone mass human syndromes Van Buchem disease and sclerosteosis, extensive animal experimentation and clinical studies demonstrated that sclerostin plays a critical role in bone homeostasis and that its deficiency or pharmacological neutralization increases bone formation. Dysregulation of sclerostin expression also underlies the pathophysiology of skeletal disorders characterized by loss of bone mass as well as the damaging effects of some cancers in bone. Thus, sclerostin has quickly become a promising molecular target for the treatment of osteoporosis and other skeletal diseases, and beneficial skeletal outcomes are observed in animal studies and clinical trials using neutralizing antibodies against sclerostin. However, the anabolic effect of blocking sclerostin decreases with time, bone mass accrual is also accompanied by anti-catabolic effects, and there is bone loss over time after therapy discontinuation. Further, the cellular source of sclerostin in the bone/bone marrow microenvironment under physiological and pathological conditions, the pathways that regulate sclerostin expression and the mechanisms by which sclerostin modulates the activity of osteocytes, osteoblasts, and osteoclasts remain unclear. In this review, we highlight the current knowledge on the regulation of Sost/sclerotin expression and its mechanism(s) of action, discuss novel observations regarding its role in signaling pathways activated by hormones and mechanical stimuli in bone, and propose future research needed to understand the full potential of therapeutic interventions that modulate Sost/sclerostin expression.