Intervertebral disc degeneration is rescued by TGFβ/BMP
signaling modulation in an ex vivo filamin B mouse model

J 2022

Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo filamin B mouse model

ZIEBA, J., K. N. FORLENZA, K. HEARD, J. H. MARTIN, Michaela BOSÁKOVÁ et. al.

Základní údaje

Originální název

Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo filamin B mouse model

Autoři

ZIEBA, J., K. N. FORLENZA, K. HEARD, J. H. MARTIN, Michaela BOSÁKOVÁ (203 Česká republika, domácí), D. H. COHN, S. P. ROBERTSON, Pavel KREJČÍ (203 Česká republika, domácí) a D. KRAKOW (garant)

Vydání

Bone research, London, SPRINGERNATURE, 2022, 2095-4700

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30402 Technologies involving the manipulation of cells, tissues, organs or the whole organism

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 12.700

Kód RIV

RIV/00216224:14110/22:00125755

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.1038/s41413-022-00200-5

UT WoS

000787774700001

Klíčová slova anglicky

Spondylocarpotarsal syndrome; TGF beta/BMP signaling modulation; mouse model

Štítky

14110513, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 16. 1. 2023 12:41, Mgr. Tereza Miškechová

Anotace

V originále

Spondylocarpotarsal syndrome (SCT) is a rare musculoskeletal disorder characterized by short stature and vertebral, carpal, and tarsal fusions resulting from biallelic nonsense mutations in the gene encoding filamin B (FLNB). Utilizing a FLNB knockout mouse, we showed that the vertebral fusions in SCT evolved from intervertebral disc (IVD) degeneration and ossification of the annulus fibrosus (AF), eventually leading to full trabecular bone formation. This resulted from alterations in the TGFβ/BMP signaling pathway that included increased canonical TGFβ and noncanonical BMP signaling. In this study, the role of FLNB in the TGFβ/BMP pathway was elucidated using in vitro, in vivo, and ex vivo treatment methodologies. The data demonstrated that FLNB interacts with inhibitory Smads 6 and 7 (i-Smads) to regulate TGFβ/BMP signaling and that loss of FLNB produces increased TGFβ receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGFβ/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGFβ/BMP pathway activity restored Flnb−/− IVD morphology. These most effective improvements resulted from specific inhibition of TGFβ and p38 signaling activation. FLNB acts as a bridge for TGFβ/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGFβ/BMP signaling that maintains the IVD. These findings further our understanding of IVD biology and reveal new molecular targets for disc degeneration as well as congenital vertebral fusion disorders.

Citovat

ZIEBA, J., K. N. FORLENZA, K. HEARD, J. H. MARTIN, Michaela BOSÁKOVÁ, D. H. COHN, S. P. ROBERTSON, Pavel KREJČÍ a D. KRAKOW. Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo filamin B mouse model. Bone research. London: SPRINGERNATURE, 2022, roč. 10, č. 1, s. 1-12. ISSN 2095-4700. Dostupné z: https://dx.doi.org/10.1038/s41413-022-00200-5.

@article{1850798,
   author = {Zieba, J. and Forlenza, K. N. and Heard, K. and Martin, J. H. and Bosáková, Michaela and Cohn, D. H. and Robertson, S. P. and Krejčí, Pavel and Krakow, D.},
   article_location = {London},
   article_number = {1},
   doi = {http://dx.doi.org/10.1038/s41413-022-00200-5},
   keywords = {Spondylocarpotarsal syndrome; TGF beta/BMP signaling modulation; mouse model},
   language = {eng},
   issn = {2095-4700},
   journal = {Bone research},
   title = {Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo filamin B mouse model},
   url = {https://www.nature.com/articles/s41413-022-00200-5},
   volume = {10},
   year = {2022}
}

TY  - JOUR
ID  - 1850798
AU  - Zieba, J. - Forlenza, K. N. - Heard, K. - Martin, J. H. - Bosáková, Michaela - Cohn, D. H. - Robertson, S. P. - Krejčí, Pavel - Krakow, D.
PY  - 2022
TI  - Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo filamin B mouse model
JF  - Bone research
VL  - 10
IS  - 1
SP  - 1-12
EP  - 1-12
PB  - SPRINGERNATURE
SN  - 20954700
KW  - Spondylocarpotarsal syndrome
KW  - TGF beta/BMP signaling modulation
KW  - mouse model
UR  - https://www.nature.com/articles/s41413-022-00200-5
N2  - Spondylocarpotarsal syndrome (SCT) is a rare musculoskeletal disorder characterized by short stature and vertebral, carpal, and tarsal fusions resulting from biallelic nonsense mutations in the gene encoding filamin B (FLNB). Utilizing a FLNB knockout mouse, we showed that the vertebral fusions in SCT evolved from intervertebral disc (IVD) degeneration and ossification of the annulus fibrosus (AF), eventually leading to full trabecular bone formation. This resulted from alterations in the TGFβ/BMP signaling pathway that included increased canonical TGFβ and noncanonical BMP signaling. In this study, the role of FLNB in the TGFβ/BMP pathway was elucidated using in vitro, in vivo, and ex vivo treatment methodologies. The data demonstrated that FLNB interacts with inhibitory Smads 6 and 7 (i-Smads) to regulate TGFβ/BMP signaling and that loss of FLNB produces increased TGFβ receptor activity and decreased Smad 1 ubiquitination. Through the use of small molecule inhibitors in an ex vivo spine model, TGFβ/BMP signaling was modulated to design a targeted treatment for SCT and disc degeneration. Inhibition of canonical and noncanonical TGFβ/BMP pathway activity restored Flnb−/− IVD morphology. These most effective improvements resulted from specific inhibition of TGFβ and p38 signaling activation. FLNB acts as a bridge for TGFβ/BMP signaling crosstalk through i-Smads and is key for the critical balance in TGFβ/BMP signaling that maintains the IVD. These findings further our understanding of IVD biology and reveal new molecular targets for disc degeneration as well as congenital vertebral fusion disorders.
ER  -

ZIEBA, J., K. N. FORLENZA, K. HEARD, J. H. MARTIN, Michaela BOSÁKOVÁ, D. H. COHN, S. P. ROBERTSON, Pavel KREJČÍ a D. KRAKOW. Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo filamin B mouse model. \textit{Bone research}. London: SPRINGERNATURE, 2022, roč.~10, č.~1, s.~1-12. ISSN~2095-4700. Dostupné z: https://dx.doi.org/10.1038/s41413-022-00200-5.

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