Fibrillin-1 Microfibrils in Organismal Physiology: Comparison
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Fibrillin-1 is the major structural component of the 10 nm-diameter microfibrils that confer key physical and mechanical properties to virtually every tissue, alone and together with elastin in the elastic fibers. Mutations in fibrillin-1 cause pleiotropic manifestations in Marfan syndrome (MFS), including dissecting thoracic aortic aneurysms, myocardial dysfunction, progressive bone loss, disproportionate skeletal growth, and the dislocation of the crystalline lens. 

  • bone lengthening
  • fibrillin-1
  • Marfan syndrome
  • thoracic aortic aneurysm

1. Thoracic Aortic Disease

The aortic matrix is organized to sustain the mechanical stresses imposed by pulsatile blood flow, with elastic and collagen fibers distributing and bearing stress, respectively [1]. Smooth muscle cells (SMCs) in the media provide contractility to the vessel, whereas endothelial cells (ECs) in the intima control vascular tone [1]. Thoracic aortic disease in MFS is characterized by the progressive widening of the aortic root and the proximal ascending aorta that increases the risk for death from an acute dissection and rupture of the vessel wall—i.e., TAAD [2]. The disease is associated with elastic fiber fragmentation (elastolysis), excessive collagen accumulation (fibrosis), dysfunctional ECs and SMCs, and localized inflammatory infiltrates [2]. Ultrastructural studies of aortas isolated from MFS mice have also revealed the loss of fibrillin-1 microfibrils that normally connect SMCs to the elastic fibers in the media, and the ECs to the internal elastic lamina in the intima [1][3]. Current protocols for TAAD management in MFS include the administration of drugs that decrease hemodynamic stress, as well as prophylactic surgery to replace the affected aortic segment [2].
While the characterization of Fbn1-null mice has implied the prominent role of fibrillin-1 microfibrils in supporting aortic tissue homeostasis during postnatal life [4], the underlying mechanism is yet to be defined due to controversial findings regarding how fibrillin-1 deficiencies may trigger TAAD formation. Early studies of aortic diseases in mice with non-lethal MFS (Fbn1C1039G/+ mice) concluded that increased TGFβ signaling is a primary consequence of a fibrillin-1 deficiency, triggering the promiscuous activation of matrix-unbound latent complexes [5]. This conclusion was based on the finding that the systemic inhibition of either TGFβ or angiotensin II signaling (via the antagonism of the type I receptor, AT1r) prevented aneurysm formation and reduced the excessive accumulation of phosphorylated (p-) Smad2 in the aorta. More recent investigations using mice with lethal MFS (Fbn1mgR/mgR mice) showed that a fibrillin-1 deficiency in the aorta actually decreased TGFβ signaling, conceivably by precluding interactions between latent complexes and activators [6]. The finding that the early postnatal deletion of the TGFβ type II receptor in the media of wild-type mice, promoting aneurysm formation, supported the notion that baseline TGFβ signaling is absolutely required to sustain the postnatal increase of systolic pressure and cardiac output [7][8]. In this view, increased p-Smad2 levels in the aneurysmal vessels of MFS mice represents a secondary consequence of fibrillin-1 deficiency, driving unproductive ECM remodeling.

2. Dilated Cardiomyopathy (DCM)

Myocardial disease and ventricular arrhythmias are additional morbidity/mortality factors in MFS. While cardiac valve disease and the stiffening of the aortic wall can promote DCM formation by imposing a volume overload on the left ventricle, several clinical studies of MFS patients have reported myocardial ventricular dysfunction in the absence of severe valvular pathology [9][10][11]. Intrinsic cardiomyopathy was also identified in both mildly and severely affected MFS mice [12][13]. Importantly, the inactivation of the Fbn1 gene in cardiomyocytes was shown to be necessary and sufficient to promote DCM formation [12]. By using a combination of genetic and pharmacological interventions, it was further shown that the underlying mechanism involves aberrant myocyte signaling by the mechanosensors AT1r and β1-integrin [12].

3. Osteopenia (OP)

Bone remodels throughout adult life through a locally coupled process of bone resorption by osteoclasts and bone formation by osteoblasts. Soluble signals released from the ECM during resorption participate in regulating different phases of bone remodeling. TGFβ is the most abundant cytokine sequestered in the bone matrix and is a critical regulator of physiological bone remodeling and repair. The absence of reliable standardized protocols to compare bone mineral density (BMD) between MFS patients and unaffected individuals, and of robust normative data for MFS children, are major contributors to ambiguity.
Fibrillin-1 microfibrils accumulate widely in skeletal tissues, including trabecular bone and marrow stroma [14]. An early one correlated OP in young MFS mice with a greater abundance of osteoclasts that also displayed increased bone resorptive activity, largely due to the TGFβ-dependent upregulation of receptor activator of nuclear factor kB ligand (RANKL) production in mutant osteoblasts [15]. This observation was later extended with the demonstration that the N-terminus fragment of fibrillin-1 can also inhibit osteoclastic resorptive activity in vitro by binding RANKL [16]. Mice deficient for fibrillin-1 in all cells derived from limb bud progenitors (Fbn1Prx-/- mice) were employed to characterize the natural history of OP in the absence of life-threatening cardiovascular complications [14]. These longitudinal analyses correlated progressive bone loss with the premature depletion of mesenchymal stem cells (MSCs) and osteoprogenitor cells, which marrow cell culture experiments associated with improper TGFβ activation [14].

4. Disproportionate Bone Lengthening

A large clinical one that monitored growth spurts and pubertal skeletal maturation in pediatric MFS patients concluded that their greater average height (relative to the general population) is probably accounted for by poorly controlled, rather than overstimulated, growth [17]. Postnatal bone lengthening progresses under the coordinated control of systemic and local signals that instruct the differentiation of epiphyseal growth plate (GP) chondrocytes.
The relative abundance of fibrillin-1 microfibrils in the perichondrium/periosteum, together with the stimulation of bone growth by periosteal resection, were originally used to argue that excessive bone lengthening in MFS may be causally related to the loss of epiphyseal constraint by a structurally impaired perichondrial matrix [18]. A different growth-regulating theory postulated that fibrillin-1 deficiency causes TGFβ hyperactivity with the result of stimulating GP chondrogenesis and, thus, bone lengthening [19]. Correlative evidence supporting this hypothetical mechanism includes the fibrillin-1 modulation of TGFβ bioavailability, microfibril accumulation around GP chondrocytes, and the TGFβ-dependent promotion of chondrogenesis in MFS patient-derived stem cells [20][21][22]. By using a combination of in vivo and ex vivo experiments, it was recently demonstrated that a fibrillin-1 deficiency in the perichondrium is causally related to a loss of local TGFβ signaling that causes dysregulated GP chondrogenesis and excessive bone lengthening (Sedes L et al. manuscript submitted).

56. Ectopia Lentis (EL)

Together with aortic aneurysms, EL represents one of the main diagnostic criteria of MFS. Fibrillin-1 is the most abundant component of the zonular fibers that anchor the lens to the ciliary body, in addition to transmitting ciliary muscle-generated forces to change focus [23]. While the identity of the cells producing the zonule proteins is yet to be fully determined, recent data from in situ hybridizations suggest that a subgroup of cells residing in the avascular portion (pars plana) of the non-pigmented ciliary epithelium (NCPE) are responsible for producing fibrillin-1 and other major structural components of the lens-holding fibers [24]. Targeted Fbn1 inactivation in the NCPE documented the structural role of fibrillin-1 microfibrils in the eye, in addition to replicating the natural history of ocular manifestations in MFS [24]. Fibrillin-1 deficiency in the NCPE was shown to result in smaller and mechanically impaired zonular fibers that eventually ruptured, causing EL in mice. Aging mutant mice developed cataracts as result of lost polarity by the unanchored fibers, which, in a few situations degenerated into glaucoma-like abnormalities [24].

References

  1. Wagenseil, J.E.; Mecham, R.P. Vascular extracellular matrix and arterial mechanics. Physiol. Rev. 2009, 89, 957–989.
  2. Milewicz, D.M.; Ramirez, F. Therapies for thoracic aortic aneurysms and acute aortic dissections. Arter. Throm. Vasc. Biol. 2019, 39, 126–136.
  3. Bunton, T.E.; Jensen Biery, N.; Gayraud, B.; Ramirez, F.; Dietz, H.C. Phenotypic modulation of vascular smooth muscle cells contributes to elastolysis in a mouse model of Marfan syndrome. Circul. Res. 2001, 88, 37–43.
  4. Carta, L.; Pereira, L.; Arteaga-Solis, E.; Lee-Arteaga, S.Y.; Lenart, B.; Starcher, B.; Merkel, C.A.; Sukoyan, M.; Kerkis, A.; Hazeki, N.; et al. Fibrillins 1 and 2 perform partially overlapping functions during aortic development. J. Biol. Chem. 2006, 281, 8016–8023.
  5. Habashi, J.P.; Judge, D.P.; Holm, T.M.; Cohn, R.D.; Loeys, B.L.; Cooper, T.K.; Myers, L.; Klein, E.C.; Liu, G.; Calvi, C.; et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006, 312, 117–121.
  6. Cook, J.R.; Clayton, N.P.; Carta, L.; Galatioto, J.; Chiu, E.; Smaldone, S.; Nelson, C.A.; Cheng, S.H.; Wentworth, B.M.; Ramirez, F. Dimorphic effects of TGFβ signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arter. Thromb. Vasc. Biol. 2015, 35, 911–917.
  7. Li, W.; Li, Q.; Jiao, Y.; Qin, L.; Ali, R.; Zhou, J.; Ferruzzi, J.; Kim, R.W.; Geirsson, A.; Dietz, H.C.; et al. Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. J. Clin. Invest 2014, 124, 755–767.
  8. Hu, J.H.; Wei, H.; Jaffe, J.; Airhart, N.; Du, L.; Angelov, S.N.; Yan, J.; Allen, J.K.; Kang, I.; Wight, T.N.; et al. Postnatal deletion of the type II transforming growth factor-β receptor in smooth muscle cells causes severe aortopathy in mice. Arter. Thromb. Vasc. Biol. 2015, 35, 2647–2656.
  9. De Backer, J.F.; Devos, D.; Segers, P.; Matthys, D.; Francois, K.; Gillebert, T.C.; De Paepe, A.M.; De Sutter, J. Primary impairment of left ventricular function in Marfan syndrome. Int. J. Cardiol. 2006, 112, 353–358.
  10. Alpendurada, F.; Wong, J.; Kiotsekoglou, A.; Banya, W.; Child, A.; Prasad, S.K.; Pennell, D.J.; Mohiaddin, R.H. Evidence for Marfan cardiomyopathy. Eur. J. Heart Fail. 2010, 12, 1085–1091.
  11. De Witte, P.; Aalberts, J.J.J.; Radonic, T.; Timmermans, J.; Scholte, A.J.; Zwinderman, A.H.; Mulder, B.J.M.; Groenink, M.; van den Berg, M.P. Intrinsic biventricular dysfunction in Marfan syndrome. Heart 2011, 97, 2063–2068.
  12. Cook, J.R.; Carta, L.; Benard, L.; Chemaly, E.R.; Chiu, E.; Rao, S.K.; Hampton, T.G.; Yurchenco, P.; Costa, K.D.; Hajjar, R.J.; et al. Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome. J. Clin. Invest 2014, 124, 1329–1339.
  13. Campens, L.; Renard, M.; Trachet, B.; Segers, P.; Mosquera, L.M.; De Sutter, J.; Sakai, L.; De Paepe, A.; De Backer, J. Intrinsic cardiomyopathy in Marfan syndrome: Results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans. Pediatr Res. 2015, 78, 256–263.
  14. Smaldone, S.; Clayton, N.; del Solar, M.; Pasqual-Gonzales, G.; Cheng, S.; Wentworth, B.; Ramirez, F. Fibrillin-1 regulates skeletal stem cell differentiation by modulating TGFβ activity within the marrow niche. J. Bone Miner. Res. 2016, 31, 86–97.
  15. Nistala, H.; Lee-Arteaga, S.; Smaldone, S.; Siciliano, G.; Ramirez, F. Extracellular microfibrils modulate osteoblast-supported osteoclastogenesis by restricting TGFβ stimulation of RANKL production. J. Biol. Chem. 2010, 285, 34126–34133.
  16. Tiedermann, K.; Boraschi-Diaz, I.; Rajakumar, I.; Kaur, J.; Roughley, P.; Reinhardt, D.P.; Komarova, S.V. Fibrillin-1 directly regulates osteoclast formation and function by a dual mechanism. J. Cell Sci. 2013, 126, 4187–4194.
  17. Erkula, G.; Jones, K.V.; Sponseller, P.D.; Dietz, H.C.; Pyeritz, R.E. Growth and maturation in Marfan syndrome. Amer. J. Genet. 2002, 109, 100–115.
  18. McKusick, V.A. Heritable Disorders of the Connective Tissue, 4th ed.; Mosby, C.V., Ed.; Mosby: St. Louis, MO, USA, 1972; pp. 61–223.
  19. Loeys, B.L.; Mortier, G.; Dietz, H.C. Bone lessons from Marfan syndrome and related disorders: Fibrillin, TGF-β and BMP at the balance of too long and too short. Pediatr. Endocrinol. Rev. 2013, 10, 417–423.
  20. Ramirez, F.; Caescu, C.; Wondimu, E.; Galatioto, J. Marfan syndrome: A connective tissue disease at the crossroads of mechanotransduction. TGFβ signaling and cell stemness. Matrix Biol. 2018, 71–72, 82–89.
  21. Keen, D.R.; Jordan, C.D.; Reinhardt, D.P.; Ridgway, C.C.; Ono, R.N.; Corson, G.M.; Fairhurst, M.L.; Sussman, M.D.; Memoli, V.A.; Sakai, L.Y. Fibrillin-1 in human cartilage: Developmental expression and formation of special banded fibers. J. Histochem. Cytochem. 1997, 45, 1069–1082.
  22. Quarto, N.; Leonard, B.; Li, S.; Marchand, M.; Anderson, E.; Behr, B.; Francke, U.; Reijo-Pera, R.; Chiao, E.; Longaker, M.T. Skeletogenic phenotype of human Marfan embryonic stem cells faithfully peoncopied by patient-specific induced-pluripotent stem cells. Proc. Natl. Acad. Sci. USA 2012, 109, 215–220.
  23. Bassnett, S. Zinns zonule. Prog. Retin. Eye Res. 2021, 82, 100902.
  24. Jones, W.; Rodriguez, J.; Bassnett, S. Targeted deletion of fibrillin-1 in the mouse eye results in ectopia lentis and other ocular phenotypes associated with Marfan syndrome. Dis. Model Mech. 2019, 12, dmm037283.
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