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Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407-11. PMID 12598898

One-paragraph summary

Marfan syndrome is caused by mutations in fibrillin-1, a matrix component of extracellular microfibrils, and a subgroup of patients has distal airspace enlargement historically called emphysema and frequently complicated by spontaneous pneumothorax. To ask how a structural matrix protein causes an apparently acquired, late-onset lung phenotype, the authors examined lungs of fibrillin-1–deficient mice — an accepted Marfan model. Lung abnormalities were evident in the immediate postnatal period and took the form of a developmental impairment of distal alveolar septation; aged mice went on to develop destructive emphysema. Fibrillin-1–deficient mice showed marked dysregulation of TGF-β activation and signalling, with resulting apoptosis in the developing lung, and perinatal antagonism of TGF-β attenuated the apoptosis and rescued alveolar septation in vivo. The authors concluded that matrix sequestration of cytokines is crucial to their regulated activation and signalling, and that perturbing this function can itself cause disease.

Key findings

  • Fibrillin-1 deficiency produces a developmental defect (failed distal alveolar septation) presenting in the immediate postnatal period, not a purely degenerative one — early developmental perturbation can predispose to a late-onset, seemingly acquired phenotype.
  • Fibrillin-1–deficient lungs show marked dysregulation of TGF-β activation and downstream signalling.
  • Excess TGF-β signalling drives apoptosis in the developing lung.
  • Perinatal TGF-β neutralisation attenuated apoptosis and rescued alveolar septation in vivo — establishing causality, not just correlation.
  • Conceptual advance: the extracellular matrix is a regulated reservoir for latent cytokines; loss of sequestration is a disease mechanism in its own right.

Limitations

  • The phenotype rescued here is pulmonary, not aortic. The extension to aortic aneurysm was an inference, made explicit only three years later in Habashi 2006 (PMID 16601194).
  • Antagonism was perinatal, addressing a developmental window; it does not establish that TGF-β blockade would help an established adult lesion.
  • TGF-β signalling readouts at the whole-tissue level cannot resolve which cell type carries the excess signalling — a distinction later shown to matter greatly, since SMC-specific TGF-β receptor loss worsens aortopathy (PMID 24401272; PMID 28119285).
  • Mouse-specific: alveolar septation timing and lung mechanics differ substantially from human.

Why it matters

This is the paper that reframed Marfan syndrome from a purely structural connective-tissue disorder into a signalling disease — and therefore into a druggable one. Together with Habashi 2006 it created the entire modern pharmacology of aortopathy (ARBs, TGF-β antagonism) and drove a decade of clinical trials. It is also the origin point of the TGF-β paradox: subsequent loss-of-function work showed that receptor-level TGF-β signalling is protective in the postnatal aorta (PMID 24401272; PMID 28119285; PMID 28729364), meaning the field must still explain how a mechanism this well demonstrated in the developing lung relates to the adult aneurysmal aorta. The unresolved task — sorting hundreds of differentially expressed genes in the Marfan aorta into protective compensations versus pathologic consequences — is the direct descendant of this paper's framing (PMID 42140666).

Cited by wiki pages

  • pathophysiology
  • animal models