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RISS 인기검색어
- 검색키워드
- 저자 : Josef M. Penninger (검색결과 3 건)
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Osteoprotegerin-Ligand in osteoporosis, arthritis, and mammary gland development
Kong, Young-Yun,Kim, Hyun-Ju,Yoon, Mi-Jeong,Josef M. Penninger 이화여자대학교 세포신호전달연구센터 2001 고사리 세포신호전달 심포지움 Vol. No.3
The morphogenesis and remodelling of bone requires the synthesis of bone matrix by osteoblasts and its coordinated resorption by osteoclasts. The TNF family molecule Osteoprotegerin-ligand(OPGL; also known as ODF, TRANCE, and RANKL) is a key factor stimulating the differentiation and activation of osteoclasts, and is therefore essential for bone remodelling and calcium mobilization from the bones. Inactivation of the opgl gene in mice results in a complete block in osteoclast development that leads to severe osteopetrosis and a failure in tooth eruption. OPGL exerts its effects on osteoclasts by binding to the TNFR family receptor RANK(receptor activator of NFkB). Osteoprotegerin(OPG) acts as a soluble decoy receptor and competes with RANK for binding to OPGL. The balance between OPGL and OPG levels determines osteoclast activation, skeletal calcium release, and bone remodelling. Abnormalities in the OPGL/RANK/OPG system lead to the increased bone resorption that underlies the bone damage of postmenopausal osteoporosis, Paget's disease, bone loss in metastatic cancers and crippling rheumatoid arthritis. In mammals, calcium transport from the mother to the fetus and neonates is a vital process to preserve the species. Mothers meet the increased requirements for calcium during pregnancy and lactation by doubling their intestinal calcium absorption and demineralizing their skeletons via activation of bone-resorbing osteoclasts. Recently we demonstrated that OPGL and RANK, the master regulators of skeletal calcium release, are essential for the formation of the lactating mammary gland, the organ required for transmission of maternal calcium to neonates in mammalian species. Moreover, we found that pregnancy hormones induce OPGL expression in mammary epithelial cells and milk protein genes, β-casein and whey acidic protein, are induced by OPGL through C/EBPβ transcriptional factor, thus a mechanism independent of STAT5.
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Receptor Activator of NF-κB Ligand Regulates the Proliferation of Mammary Epithelial Cells via Id2
Kim, Nam-Shik,Kim, Hyun-Ju,Koo, Bon-Kyoung,Kwon, Min-Chul,Kim, Young-Woong,Cho, Yunje,Yokota, Yoshifumi,Penninger, Josef M.,Kong, Young-Yun American Society for Microbiology 2006 Molecular and cellular biology Vol.26 No.3
<B>ABSTRACT</B><P>Receptor activator of NF-κB ligand (RANKL) is a key regulator for mammary gland development during pregnancy. RANKL-deficient mice display impaired development of lobulo-alveolar mammary structures. Similar mammary gland defects have been reported in mice lacking Id2. Here we report that RANKL induces the proliferation of mammary epithelial cells via Id2. RANKL triggers marked nuclear translocation of Id2 in mammary epithelial cells. In vivo studies further demonstrated the defective nuclear translocation of Id2, but the normal expression of cyclin D1, in the mammary epithelial cells of <I>rankl</I><SUP><I>−/−</I></SUP> mice. In vitro studies with nuclear localization sequence-tagged Id2 revealed that the nuclear localization of Id2 itself is critical for the downregulation of p21 promoter activity. Moreover, RANKL stimulation failed to induce cell growth and to downregulate p21 expression in <I>Id2</I><SUP><I>−/−</I></SUP> mammary epithelial cells. Our results indicate that the inhibitor of helix-loop-helix protein, Id2, is critical to control the proliferation of mammary epithelial cells in response to RANKL stimulation.</P>
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CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts
Greenblatt, Matthew B.,Park, Kwang Hwan,Oh, Hwanhee,Kim, Jung-Min,Shin, Dong Yeon,Lee, Jae Myun,Lee, Jin Woo,Singh, Anju,Lee, Ki-young,Hu, Dorothy,Xiao, Changchun,Charles, Julia F.,Penninger, Josef M. The Rockefeller University Press 2015 The Journal of experimental medicine Vol.212 No.8
<▼1><P>Greenblatt et al. show that deletion of CHMP5 in osteoclasts leads to increased bone resorption coupled with exuberant osteoblast activity, resembling an early onset form of human Paget’s Disease of Bone</P></▼1><▼2><P>Physiological bone remodeling requires that bone formation by osteoblasts be tightly coupled to bone resorption by osteoclasts. However, relatively little is understood about how this coupling is regulated. Here, we demonstrate that modulation of NF-κB signaling in osteoclasts via a novel activity of charged multivesicular body protein 5 (CHMP5) is a key determinant of systemic rates of bone turnover. A conditional deletion of CHMP5 in osteoclasts leads to increased bone resorption by osteoclasts coupled with exuberant bone formation by osteoblasts, resembling an early onset, polyostotic form of human Paget’s disease of bone (PDB). These phenotypes are reversed by haploinsufficiency for <I>Rank</I>, as well as by antiresorptive treatments, including alendronate, zolendronate, and OPG-Fc. Accordingly, CHMP5-deficient osteoclasts display increased RANKL-induced NF-κB activation and osteoclast differentiation. Biochemical analysis demonstrated that CHMP5 cooperates with the PDB genetic risk factor valosin-containing protein (VCP/p97) to stabilize the inhibitor of NF-κBα (IκBα), down-regulating ubiquitination of IκBα via the deubiquitinating enzyme USP15. Thus, CHMP5 tunes NF-κB signaling downstream of RANK in osteoclasts to dampen osteoclast differentiation, osteoblast coupling and bone turnover rates, and disruption of CHMP5 activity results in a PDB-like skeletal disorder.</P></▼2>
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