Elastin & Connective Tissue
What is elastin?
Elastin is an elastic protein protein found in elastic fibers (dermis, lungs, vessels, & ligaments → anywhere where stretch is necessary). Yes, Type 2 collagen (Elastic collagen) has elastin present.
What gene mutation is responsible for Marfan syndrome, and what protein does it encode?
FBN1 gene → encoding for fibrillin protein (fibrillin-1).
Is there a cure for Marfan’s?
No, only management of symptoms
What does TGF-B stand for?
Transforming Growth Factor-Beta
What breaks down elastic fibers?
Elastase breaks down elastin in the body.
Alpha-1 anti-trypsin regulates elastase activity (deficiency in alpha-1 anti-trypsin results in panancinar emphysema).
What is the inheritance pattern of Marfan’s Syndrome?
Autosomal Dominant (but, there is variable penetrance)
What is the incidence of Marfan’s? Also, what is incidence?
1 in every 3,000-5,000.
Incidence is # of new individuals expressing disease or charactertistic during specific interval of time.
What role does TGF-B play in the body?
TGF-B regulates proliferation (promote cell arrest & tumor suppressor activiy ), differentiation, apoptosis, & is very important in overall maintenance of ECM integrity
What are the 3 main fiber types of connective tissue?
1) Collagen Fibers (Most commonly Type 1 collagen → provide tensile strength to dense & loose connective tissue)
2) Reticular Fibers (Type 3 collagen → cross link to form reticular layer of basement membranes in liver, bone marrow, spleen, & lymph nodes)
3) Elastic Fibers (Type 2 collagen & Elastin that provide ability to stretch in blood vessels, dermis, lungs, & ligaments).
What are 3 classic clinical presentations of Marfan’s?
= Arachnodactyly, Spinal Deformities, Pectus Excavatum, Hyperextensibility, Craniofacial features, Predisposition to Heart Disease, & Ectopia lentis (subluxation (misalignment) of lens forward & up)
What is used for diagnoses of Marfan’s?
Ghent Criteria & Genetic Testing (for FBN1 gene).
How are fibrillin-1 and TGF-B availability related?
Mutated FBN-1 protein results in abnormal fibrillin production & therefore abnormal elastic fibers. Fibrillin-1 helps sequester & regulate TGF-β activity in the ECM (keeping it in its inactive form), but mutations in the FBN1 gene lead to increased bioavailability of TGF-β (& its consequential negative effects).
What is the precursor to elastin (bonus points if the 3 amino acids are named)?
Precursor to elastin is called tropoelastin, which is made of glycine, proline, & lysine (non-glycosylated).
What are common Heart Conditions associated with Marfans (connect to pathogenesis)?
Aortic Dissection, Aneurysm, & Mitral Valve Prolapse. Blood vessels require elastic fibers for proper functioning to withstand the stretch of increased blood pressures. If there is defective fibrillin, then there is not proper cross-linking of tropoelastin & improper maturation to elastin fibers. This in combination with unregulated TGF-B activity reduces structural integrity of these vessels.
What activities should be avoided with Marfan’s patients?
Contact sports, excessive & vigorous exercise, avoiding surgeries, limit or avoid drug consumption (caffeine, nicotine, alcohol, smoking), regular health monitoring, & positive pressure ventilation (large brass instruments), & caution with childbearing.
How does TGF-B mediated ROS production degrade ECM?
Increased TGF-β signaling elevates ROS (particularly NADPH oxidases) which directly damage elastin and collagen through oxidative modifications. ROS also upregulate MMP & proinflammatory cytokine activity. There is also a decrease in selenium & thioredoxin which are important in the antioxidant defense system (reducing the body’s ability to neutralize the ROS).
How are elastic fibers made?
Tropoelastin is translated (made of proline, glycine, & lysine) & is cross-linked with fibrillin. The proper cross-linking of tropoelastin allow for maturation into elastin fibers (found in connective tissues & the ECM).
What is the pathophysiology of Marfan’s Syndrome?
Mutated FBN1 (which encodes for fibrillin) → defective fibrillin means there is not proper cross-linking of elastin & results in defective elastin fibers. This causes reduced structural integrity of those tissues where elastic fibers are found.
Mutated fibrillin & consequential elastic fibers also prevent proper sequestration & regulation of TGF-B. Increased TGF-B activity elevates metalloproteinase activity (MMPs), releases pro-inflammatory cytokines, & mediate the accumulation of reactive oxidative species.
What are common supportive therapies for Marfan’s complications?
Pain management (analgesia), surgery or bracing for scoliosis, & antihypertensives (B-blockers, ACEi, ARBs)
How does increased TGF-β signaling impact Marfan syndrome symptoms?
Increased bioavailability & dysregulation of TGF-β signaling promotes ECM degradation through increased metalloproteinase activity (MMPs), MMPS-2 & MMP-9 are ECM degeradatory proteins that break down collaged & elastin, contributing to degeneration of blood vessel walls (decreased structure) & risk of heart conditions such as aortic dissection & aneurysm. TGF beta is also found to have a role in inflammatory pathways (releasing pro-inflammatory cytokines) & mediate the accumulation of reactive oxidative species (exacerbating degradation).