Molecular pathogenesis of Marfan Syndrome
- Intake: OxKEN
Background: Marfan Syndrome (MFS) is an autosomal dominant condition occurring in one in 5,000-10,000 individuals. It is driven by mutations in fibrillin-1 (FBN1), an extracellular matrix (ECM) protein, that forms part of the elastin rich filament of large arteries. This can result in aortic dissection, the principal life-threatening complication of MFS. In recent years it has emerged that loss of fibrillin-1, rather than simply causing weakness of the matrix, alters the bioavailability of a key repair growth factor, TGFb. Targeting TGFb arrests aortic dilation in mice with MFS and improves vascular outcomes in patients (1, 2). This, combined with regular surveillance (echocardiography) and improved surgical repair, means that the life expectancy in MFS has greatly increased.
Musculoskeletal complications in MFS are common and cause significant disability, increasingly so in the ageing patient population. In addition to disproportionately long arms and legs, changes include scoliosis, chest wall deformities and hind foot abnormalities. In young individuals with MFS, complaints are often around deformity, affecting self-esteem, posture and ability to cope with the diagnosis. In older individuals, pain may occur as osteoarthritis develops at stress points e.g. the concavity of the scoliotic spine.
We have recently performed detailed characterisation of the skeletons of mice with a human knock-in fibrillin-1 mutation, and shown that they exhibit all of the expected features of disease including long arms and legs, kyphoscoliosis, chest wall abnormalities and hypognathism (small jaw) (unpublished data) (Figure 1). Previously our group has described a number of matrix bound growth factors that are sequestered in the pericellular matrix of articular cartilage and released in response to injury (3-5). Pilot microscopy data of the growth plates of MFS mice indicate that the growth plate is of normal size but there is a reduction in matrix bound latent TGFb that is normally apparent prominent around the hypertrophic chondrocytes. TGFb co-localises with perlecan, a heparan sulfate proteoglycan, similar to what we have seen in articular cartilage. A number of important questions have emerged:
- What is the temporal development of the skeletal abnormalities in MFS mice pre-and post-natally?
- Is there aberrant TGFb signalling in the growth plate (as seen in the aortas) and to what extent is this driving the skeletal phenotype?
- Are other perlecan bound growth factors also affected in MFS (e.g. FGF2) and does this contribute to pathobiology of disease?
- Are the musculoskeletal features of MFS amenable to pharmacological intervention, and if so, what is the optimal treatment window?
Figure 1. Musculoskeletal features of mice carrying a human type mutation in fibrillin-1.
MicroCT images were taken of wild type (WT) and MFS mice (HET) at either 9 or 45 weeks of age. Lateral views of mice show excessive kyphosis in HET which is quantified as a reduced distance from the peak of kyphosis to first rib (kyphosis length). Dorsal view shows abnormal rib cage, and increased tibial length. Immunohistochemistry showing latent TGFb (LAP) and perlecan in the growth plate (between hashed and solid white lines) of WT and HET mice. Note distinctive LAP staining in basal cells of WT mice that is less lost in HETs.
The student will be embedded within the Kennedy Institute of Rheumatology where they will interact with clinical and non-clinical scientists working across inflammatory and other rheumatological diseases. They will be part of a large multidisciplinary cohort of DPhil students at the Kennedy and the wider NDORMS, and take advantage of multiple training opportunities through seminars and departmental and University courses. They will present their data regularly to group and Centre meetings. If desired, they will have the opportunity to attend bi-monthly MFS clinics in Oxford with Vincent.
Growth plate biology
TGFb and FGF2 signalling
- Characterisation of the phenotype of MFS in vivo using ex vivo tissue, microCT scanning.
- Confocal microscopy of long bone growth plates.
- In vivo protein turnover studies including SILAC labelling and proteomics.
- RNA Scope (in situ RNA labelling of individual cells within the growth plate).
- Design of a pharmacological trial in mice to test whether the skeletal complications in MFS are modifiable.
- M. M. van Andel et al., Long-term clinical outcomes of losartan in patients with Marfan syndrome: follow-up of the multicentre randomized controlled COMPARE trial. Eur Heart J 10.1093/eurheartj/ehaa377 (2020).
- M. Mullen et al., Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial. Lancet 394, 2263-2270 (2019).
- X. Tang et al., Connective tissue growth factor contributes to joint homeostasis and osteoarthritis severity by controlling the matrix sequestration and activation of latent TGFβ. Annals of the rheumatic diseases 10.1136/annrheumdis-2018-212964 (2018).
- T. Vincent, M. Hermansson, M. Bolton, R. Wait, J. Saklatvala, Basic FGF mediates an immediate response of articular cartilage to mechanical injury. Proc Natl Acad Sci U S A 99, 8259-8264 (2002).
- T. L. Vincent, C. J. McLean, L. E. Full, D. Peston, J. Saklatvala, FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer. YJOCA 15, 752-763 (2007).