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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>
Osteoimmunology: A Brief Introduction
Greenblatt, Matthew B.,Shim, Jae-Hyuck The Korean Association of Immunobiologists 2013 Immune Network Vol.13 No.4
Recent investigations have demonstrated extensive reciprocal interactions between the immune and skeletal systems, resulting in the establishment of osteoimmunology as a cross-disciplinary field. Here we highlight core concepts and recent advances in this emerging area of study.
The Extracellular Signal-Regulated Kinase Mitogen- Activated Protein Kinase Pathway in Osteoblasts
Matthew B. Greenblatt,Jae-Hyuck Shim,복서연,Jung-Min Kim 대한골대사학회 2022 대한골대사학회지 Vol.29 No.1
Extracellular signal-regulated kinases (ERKs) are evolutionarily ancient signal transduc- ers of the mitogen-activated protein kinase (MAPK) family that have long been linked to the regulation of osteoblast differentiation and bone formation. Here, we review the physiological functions, biochemistry, upstream activators, and downstream substrates of the ERK pathway. ERK is activated in skeletal progenitors and regulates osteoblast dif- ferentiation and skeletal mineralization, with ERK serving as a key regulator of Runt-re- lated transcription factor 2, a critical transcription factor for osteoblast differentiation. However, new evidence highlights context-dependent changes in ERK MAPK pathway wiring and function, indicating a broader set of physiological roles associated with changes in ERK pathway components or substrates. Consistent with this importance, several human skeletal dysplasias are associated with dysregulation of the ERK MAPK pathway, including neurofibromatosis type 1 and Noonan syndrome. The continually broadening array of drugs targeting the ERK pathway for the treatment of cancer and other disorders makes it increasingly important to understand how interference with this pathway impacts bone metabolism, highlighting the importance of mouse studies to model the role of the ERK MAPK pathway in bone formation.
Osteoimmunology: A Brief Introduction
Matthew B. Greenblatt,Jae-Hyuck Shim 대한면역학회 2013 Immune Network Vol.13 No.4
Recent investigations have demonstrated extensive reciprocal interactions between the immune and skeletal systems, resulting in the establishment of osteoimmunology as a cross-disciplinary field. Here we highlight core concepts and recent advances in this emerging area of study.
Shim, Jae-Hyuck,Greenblatt, Matthew B,Singh, Anju,Brady, Nicholas,Hu, Dorothy,Drapp, Rebecca,Ogawa, Wataru,Kasuga, Masato,Noda, Tetsuo,Yang, Sang-Hwa,Lee, Sang-Kyou,Rebel, Vivienne I,Glimcher, Laurie American Society for Clinical Investigation 2012 The Journal of clinical investigation Vol.122 No.1
<P>Mutations in the coactivator CREB-binding protein (CBP) are a major cause of the human skeletal dysplasia Rubinstein-Taybi syndrome (RTS); however, the mechanism by which these mutations affect skeletal mineralization and patterning is unknown. Here, we report the identification of 3-phosphoinositide-dependent kinase 1 (PDK1) as a key regulator of CBP activity and demonstrate that its functions map to both osteoprogenitor cells and mature osteoblasts. In osteoblasts, PDK1 activated the CREB/CBP complex, which in turn controlled runt-related transcription factor 2 (RUNX2) activation and expression of bone morphogenetic protein 2 (BMP2). These pathways also operated in vivo, as evidenced by recapitulation of RTS spectrum phenotypes with osteoblast-specific Pdk1 deletion in mice (Pdk1osx mice) and by the genetic interactions observed in mice heterozygous for both osteoblast-specific Pdk1 deletion and either Runx2 or Creb deletion. Finally, treatment of Pdk1osx and Cbp+/- embryos with BMPs in utero partially reversed their skeletal anomalies at birth. These findings illustrate the in vivo function of the PDK1-AKT-CREB/CBP pathway in bone formation and provide proof of principle for in utero growth factor supplementation as a potential therapy for skeletal dysplasias.</P>
S6K1 Negatively Regulates TAK1 Activity in the Toll-Like Receptor Signaling Pathway
Kim, So Yong,Baik, Kyung-Hwa,Baek, Kwan-Hyuck,Chah, Kyong-Hwa,Kim, Kyung Ah,Moon, Gyuyoung,Jung, Eunyu,Kim, Seong-Tae,Shim, Jae-Hyuck,Greenblatt, Matthew B.,Chun, Eunyoung,Lee, Ki-Young American Society for Microbiology 2014 Molecular and cellular biology Vol.34 No.3
<P>Transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) is a key regulator in the signals transduced by proinflammatory cytokines and Toll-like receptors (TLRs). The regulatory mechanism of TAK1 in response to various tissue types and stimuli remains incompletely understood. Here, we show that ribosomal S6 kinase 1 (S6K1) negatively regulates TLR-mediated signals by inhibiting TAK1 activity. S6K1 overexpression causes a marked reduction in NF-κB and AP-1 activity induced by stimulation of TLR2 or TLR4. In contrast, S6K1<SUP>−/−</SUP> and S6K1 knockdown cells display enhanced production of inflammatory cytokines. Moreover, S6K1<SUP>−/−</SUP> mice exhibit decreased survival in response to challenge with lipopolysaccharide (LPS). We found that S6K1 inhibits TAK1 kinase activity by interfering with the interaction between TAK1 and TAB1, which is a key regulator protein for TAK1 catalytic function. Upon stimulation with TLR ligands, S6K1 deficiency causes a marked increase in TAK1 kinase activity that in turn induces a substantial enhancement of NF-κB-dependent gene expression, indicating that S6K1 is negatively involved in the TLR signaling pathway by the inhibition of TAK1 activity. Our findings contribute to understanding the molecular pathogenesis of the impaired immune responses seen in type 2 diabetes, where S6K1 plays a key role both in driving insulin resistance and modulating TLR signaling.</P>