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Title: TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions}
Article:
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.
Introduction:
Skeletal dysplasias are a heterogeneous group of more than 450 disorders characterized by abnormalities in patterning, development, and maintenance of the skeleton[1]. Congenital vertebral deformities in some of these disorders, particularly those that lead to progressive fusions, cause chronic pain and deformity and the mechanisms underlying the development of these fusions are poorly understood. 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]. The vertebral fusions can occur prenatally, leading to the appearance of an ectopic bar of bone spanning multiple vertebral bodies at birth[3]. 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 ultimately 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). The IVD forms a fibrous joint that functions as a shock absorber for the spine and allows for slight flexion. 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. The process of endochondral ossification requires the coordination of multiple signaling pathways. TGFβ/BMP signaling is essential for early cartilage and bone formation as well as postnatal growth[4, 5]. The BMP and TGFβ pathways signal via their canonical receptor phosphorylated Smads( R-Smads)[6, 7]. The TGFβ pathway signals through R-Smads 2 and 3 while the BMP pathway utilizes R-Smads 1, 5, and 8. Upon ligand binding the receptors phosphorylate and activate the R-Smads. The activated R-Smads translocate to the nucleus and form complexes with additional proteins to induce or repress target gene transcription. Both pathways also utilize the MAPK/ERK and TAK1/p38 pathways as non-canonical signaling pathways. Misregulation of TGFβ and BMP signaling affects many aspects of skeletal development, including formation of the IVD[8], and over-activation of these pathways has been shown to cause ectopic bone formation in several tissues[9–11]. The IVD AF, as well as cartilage, ligament, and tendon tissues, are derived from progenitor pools consisting of distinct cell populations with unique expression profiles. While TGFβ and BMP signaling are critically important in musculoskeletal tissues, studies have recently shown that each of these distinct cell populations responds differently to changes in these respective signaling pathways[12]. Filamins are cytoskeletal proteins that stabilize actin filament networks and link them to the cellular membrane, thus forming a scaffold for integrating cell mechanics and signaling[13]. Filamins have also been shown to interact directly with Smads 2 and 3, as well as 1 and 5, central mediators of canonical TGFβ and BMP signaling, respectively[14, 15]. FLNB is expressed throughout the cartilage growth plate as well as in the cartilaginous condensations of developing vertebrae[16]. Biallelic loss of function mutations leading to loss of FLNB cause SCT, while heterozygosity for missense mutations in FLNB produces a spectrum of autosomal dominant skeletal disorders including boomerang dysplasia( OMIM 112310); Larsen syndrome( OMIM 150250); and atelosteogenesis I and III( AOI, OMIM 108720; AOIII, OMIM 108721). In this study we used mice homozygous for a gene trapped Flnb allele( Flnb–/–)[17]. We previously showed that Flnb–/–mice phenocopy SCT and show progressive vertebral, carpal, tarsal, and sternal fusions as well as smaller overall body size, making this an ideal animal model for studying progressive vertebral fusions[17]. Mice heterozygous for the gene trap are unaffected. FLNB is expressed in the developing skeleton, throughout the growth plate, in the developing limb buds and between the neural arches of the vertebrae[17] as well as in the somites, which include the cells destined to become the vertebral bodies and IVDs of the spine. It was initially hypothesized that SCT vertebral fusions resulted from failure to segment the vertebrae properly[18, 19], but analysis of the Flnb knockout mouse model demonstrated that the vertebrae form normally but subsequently fuse[17]. In this study, we seek to explain how absence of FLNB produces spinal fusions, the most compelling phenotypic finding in both humans and mice. We demonstrate that in the absence of FLNB, TGFβ and BMP signaling is increased both in vitro and in vivo, demonstrating that FLNB is required for the attenuation of TGFβ/BMP signaling. We also show that the mutant AF undergoes ectopic differentiation toward a chondrogenic lineage in the IVD, leading to abnormal endochondral ossification. The phenotypic findings resemble those seen in aging disc degeneration and therefore provide a developmental model for degenerative disc disease.
Discussion:
In our study, we demonstrated that loss of FLNB in a mouse models produces an alteration in AF cells from a fibrous to a cartilaginous fate and disruption of the nucleus pulposus, leading to degeneration, subsequent collapse of the disc followed by fusion of the flanking vertebral bodies. This phenotype results from inappropriate up-regulation of the TGFβ canonical and BMP non-canonical pathways. Previous studies have interpreted that the observed increases in TGFβ/BMP signaling within degenerative discs occur as an effort to repair the extracellular matrix[40]. Because elevated p-Smad2 and 3 were observed in chondrocytes prior to IVD disc degeneration, our model suggests that increased TGFβ and BMP signaling as a consequence of loss of FLNB initiates the cascade of cell fate changes including differentiation, subsequent IVD degeneration and bony fusions. This study has revealed the cascade of some molecular mechanisms governing the development of vertebral fusions and postnatal disc maintenance and degeneration, providing insights which may direct studies that lead to rationale targets for therapeutic solutions.
Whereas there is a large foundation of knowledge concerning skeletal formation and development , identifying the molecular changes behind Intervertebral Disc ( IVD ) aging and degeneration has been a challenge . The loss of Filamin B , a protein component of the cell’s cytoskeletal structure , gives rise to Spondylocarpotarsal Synostosis , a rare genetic disorder characterized by fusions of the vertebral bodies . Similarly , mice lacking the Filamin B protein show fusions of the vertebral bodies . We found that these fusions are caused by the early degeneration and eventual ossification of the IVDs . Our study demonstrates that this degeneration is caused by the increase in TGFβ and BMP activity , developmental pathways essential in bone and cartilage formation . These findings represent a significant step forward in our understanding of the molecular basis of IVD degeneration . as well as revealing filamin B’s role in TGFβ/BMP signaling regulation . Moreover , we demonstrate that the study of the rare disease spondylocarpotarsal synostosis in a model organism can uncover mechanisms underlying more common diseases . Finally , our findings provide a model system that will facilitate further discoveries regarding disc degeneration , which affects a significant proportion of the population .