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.
Highlights
Skeletal dysplasias are a heterogeneous group of more than 450 disorders characterized by abnormalities in patterning, development, and maintenance of the skeleton [1]
We have shown that annulus fibrosus (AF) cells adopt gene expression patterns of hypertrophic chondrocytes in the Flnb allele (Flnb–/–)intervertebral discs (IVDs), we further sought to determine if these findings result from transformation of AF cells as opposed to invasion by chondrocytes
The transforming Flnb–/–cells continue to express the AF marker SCX, showing that the observed hypertrophic cells are inappropriately transformed AF cells. This suggests that the AF cells in the IVD of Flnb–/–mice undergo an inappropriate transition from fibroblast-like to chondrocytic cells, culminating in transition to terminally differentiated chondrocytes that undergo apoptosis
Summary
Skeletal dysplasias are a heterogeneous group of more than 450 disorders characterized by abnormalities in patterning, development, and maintenance of the skeleton [1]. Spondylocarpotarsal synostosis (SCT) syndrome is a recessively inherited disorder caused by nonsense mutations in Filamin B (FLNB); it is characterized by progressive vertebral, carpal, and tarsal bone fusions, short stature, and scoliosis [2]. Development of the axial skeleton, including the vertebral bodies, occurs via the process of endochondral bone formation, in which a cartilage template is replaced by bone. Endochondral bone growth occurs through the cartilage growth plate, a stratified tissue consisting of reserve, resting, proliferating, and hypertrophic chondrocytes which undergo apoptosis, leaving voids that become inhabited by osteoblasts forming the primary spongiosa. Vertebral bodies of the axial skeleton develop through endochondral ossification and are separated from each other by intervertebral discs (IVDs). Each IVD consists of two functional domains: the inner gel-like center of the nucleus pulposus and the outer fibrous tissue of the annulus fibrosus (AF). At the interface between the IVD and the vertebral body lies the endplate, a transitional tissue of mineralized matrix surrounding hypertrophic-like chondrocytes
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