TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions.

Abstract

Spondylocarpotarsal synostosis (SCT) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in Filamin B (FLNB). FLNB acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems, yet the disease mechanisms for SCT remain unclear. Employing a Flnb knockout mouse, we found morphologic and molecular evidence that the intervertebral discs (IVDs) of Flnb-/-mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the IVD, particularly the annulus fibrosus (AF). In Flnb-/-mice, the AF cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue. We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFβ signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf. These findings indicate that FLNB is involved in attenuation of TGFβ/BMP signaling and influences AF cell fate. Furthermore, we demonstrate that the IVD disruptions in Flnb-/-mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration.

• Authors: Jennifer Zieba, Kimberly Nicole Forlenza, Jagteshwar Singh Khatra, Anna Sarukhanov, Ivan Duran, Diana Rigueur, Karen M Lyons, Daniel H Cohn, Amy E Merrill, Deborah Krakow
• Journal: PLoS genetics (PLoS Genet) Vol. 12 Issue 3 Pg. e1005936 (Mar 2016) ISSN: 1553-7404 [Electronic] United States
• PMID: 27019229 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Bone Morphogenetic Proteins
• CCN2 protein, mouse
• Filamins
• Smad Proteins
• Transforming Growth Factor beta
• Connective Tissue Growth Factor

Topics

• Abnormalities, Multiple (genetics, pathology)
• Actin Cytoskeleton (genetics, metabolism)
• Animals
• Bone Morphogenetic Proteins (genetics, metabolism)
• Chondrocytes (metabolism, pathology)
• Connective Tissue Growth Factor (genetics, metabolism)
• Disease Models, Animal
• Filamins (genetics)
• Growth Plate (growth & development, pathology)
• Humans
• Intervertebral Disc Degeneration (genetics, pathology)
• Lumbar Vertebrae (abnormalities, pathology)
• Mice
• Mice, Knockout
• Musculoskeletal Diseases (genetics, pathology)
• Scoliosis (congenital, genetics, pathology)
• Signal Transduction
• Smad Proteins (genetics, metabolism)
• Spine (growth & development, pathology)
• Synostosis (genetics, pathology)
• Thoracic Vertebrae (abnormalities, pathology)
• Transforming Growth Factor beta (genetics)