Attenuation of NF-κB in Intestinal Epithelial Cells Is Sufficient to Mitigate the Bone Loss Comorbidity of Experimental Mouse Colitis
© 2019 American Society for Bone and Mineral Research..
Skeletal abnormalities are common comorbidities of inflammatory bowel disease (IBD). Patients suffering from IBD, including ulcerative colitis and Crohn's disease, present with skeletal complications. However, the mechanism underpinning IBD-associated bone loss remains vague. Intestinal inflammation generates an inflammatory milieu at the intestinal epithelium that leads to dysregulation of mucosal immunity through gut-residing innate lymphoid cells (ILCs) and other cell types. ILCs are recently identified mucosal cells considered as the gatekeeper of gut immunity and their function is regulated by intestinal epithelial cell (IEC)-secreted cytokines in response to the inflammatory microenvironment. We first demonstrate that serum as well as IECs collected from the intestine of dextran sulfate sodium (DSS)-induced colitis mice contain high levels of inflammatory and osteoclastogenic cytokines. Mechanistically, heightened inflammatory response of IECs was associated with significant intrinsic activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in IECs and increased frequency of ILC1, ILC3, and myeloid osteoclast progenitors. Validating the central role of IEC-specific NF-κB activation in this phenomenon, conditional expression of constitutively active inhibitor kappa B kinase 2 (IKK2) in IECs in mice recapitulates the majority of the cellular, inflammatory, and osteolytic phenotypes observed in the chemically induced colitis. Furthermore, conditional deletion of IKK2 from IECs significantly attenuated inflammation and bone loss in DSS-induced colitis. Finally, using the DSS-induced colitis model, pharmacologic inhibition of IKK2 was effective in reducing frequency of ILC1 and ILC3 cells, attenuated circulating levels of inflammatory cytokines, and halted colitis-associated bone loss. Our findings identify IKK2 in IECs as viable therapeutic target for colitis-associated osteopenia.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:34 |
|---|---|
| Enthalten in: |
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research - 34(2019), 10 vom: 01. Okt., Seite 1880-1893 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ke, Ke [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 04.09.2020 Date Revised 14.10.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1002/jbmr.3759 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM297260359 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM297260359 | ||
| 003 | DE-627 | ||
| 005 | 20231225091615.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/jbmr.3759 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0990.xml |
| 035 | |a (DE-627)NLM297260359 | ||
| 035 | |a (NLM)31107556 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ke, Ke |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Attenuation of NF-κB in Intestinal Epithelial Cells Is Sufficient to Mitigate the Bone Loss Comorbidity of Experimental Mouse Colitis |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 04.09.2020 | ||
| 500 | |a Date Revised 14.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2019 American Society for Bone and Mineral Research. | ||
| 520 | |a Skeletal abnormalities are common comorbidities of inflammatory bowel disease (IBD). Patients suffering from IBD, including ulcerative colitis and Crohn's disease, present with skeletal complications. However, the mechanism underpinning IBD-associated bone loss remains vague. Intestinal inflammation generates an inflammatory milieu at the intestinal epithelium that leads to dysregulation of mucosal immunity through gut-residing innate lymphoid cells (ILCs) and other cell types. ILCs are recently identified mucosal cells considered as the gatekeeper of gut immunity and their function is regulated by intestinal epithelial cell (IEC)-secreted cytokines in response to the inflammatory microenvironment. We first demonstrate that serum as well as IECs collected from the intestine of dextran sulfate sodium (DSS)-induced colitis mice contain high levels of inflammatory and osteoclastogenic cytokines. Mechanistically, heightened inflammatory response of IECs was associated with significant intrinsic activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in IECs and increased frequency of ILC1, ILC3, and myeloid osteoclast progenitors. Validating the central role of IEC-specific NF-κB activation in this phenomenon, conditional expression of constitutively active inhibitor kappa B kinase 2 (IKK2) in IECs in mice recapitulates the majority of the cellular, inflammatory, and osteolytic phenotypes observed in the chemically induced colitis. Furthermore, conditional deletion of IKK2 from IECs significantly attenuated inflammation and bone loss in DSS-induced colitis. Finally, using the DSS-induced colitis model, pharmacologic inhibition of IKK2 was effective in reducing frequency of ILC1 and ILC3 cells, attenuated circulating levels of inflammatory cytokines, and halted colitis-associated bone loss. Our findings identify IKK2 in IECs as viable therapeutic target for colitis-associated osteopenia | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a BONE LOSS | |
| 650 | 4 | |a COLITIS | |
| 650 | 4 | |a IECS | |
| 650 | 4 | |a ILCS | |
| 650 | 4 | |a INFLAMMATION | |
| 650 | 4 | |a INTESTINE | |
| 650 | 4 | |a NF-κB | |
| 650 | 7 | |a NF-kappa B |2 NLM | |
| 650 | 7 | |a Dextran Sulfate |2 NLM | |
| 650 | 7 | |a 9042-14-2 |2 NLM | |
| 650 | 7 | |a I-kappa B Kinase |2 NLM | |
| 650 | 7 | |a EC 2.7.11.10 |2 NLM | |
| 650 | 7 | |a Ikbkb protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.7.11.10 |2 NLM | |
| 700 | 1 | |a Chen, Tim Hung-Po |e verfasserin |4 aut | |
| 700 | 1 | |a Arra, Manoj |e verfasserin |4 aut | |
| 700 | 1 | |a Mbalaviele, Gabriel |e verfasserin |4 aut | |
| 700 | 1 | |a Swarnkar, Gaurav |e verfasserin |4 aut | |
| 700 | 1 | |a Abu-Amer, Yousef |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research |d 1991 |g 34(2019), 10 vom: 01. Okt., Seite 1880-1893 |w (DE-627)NLM012611115 |x 1523-4681 |7 nnns |
| 773 | 1 | 8 | |g volume:34 |g year:2019 |g number:10 |g day:01 |g month:10 |g pages:1880-1893 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/jbmr.3759 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 34 |j 2019 |e 10 |b 01 |c 10 |h 1880-1893 | ||