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, D. H. COHN, S. P. ROBERTSON, Pavel KREJČÍ and 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, vol. 10, No 1, p. 1-12. ISSN 2095-4700. Available from: https://dx.doi.org/10.1038/s41413-022-00200-5.

Basic information

• Original name: Intervertebral disc degeneration is rescued by TGFβ/BMP signaling modulation in an ex vivo filamin B mouse model
• Authors: ZIEBA, J., K. N. FORLENZA, K. HEARD, J. H. MARTIN, Michaela BOSÁKOVÁ (203 Czech Republic, belonging to the institution), D. H. COHN, S. P. ROBERTSON, Pavel KREJČÍ (203 Czech Republic, belonging to the institution) and D. KRAKOW (guarantor).
• Edition: Bone research, London, SPRINGERNATURE, 2022, 2095-4700.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30402 Technologies involving the manipulation of cells, tissues, organs or the whole organism
• Country of publisher: United Kingdom of Great Britain and Northern Ireland
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 12.700
• RIV identification code: RIV/00216224:14110/22:00125755
• Organization unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.1038/s41413-022-00200-5
• UT WoS: 000787774700001
• Keywords in English: Spondylocarpotarsal syndrome; TGF beta/BMP signaling modulation; mouse model
• Tags: 14110513, rivok
• Tags: International impact, Reviewed

Abstract

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.