Elastic Fibers in Orthopaedics: Form and Function in Tendons and Ligaments, Clinical Implications, and Future Directions

Abstract

Elastic fibers are an essential component of the extracellular matrix of connective tissues. The focus of both clinical management and scientific investigation of elastic fiber disorders has centered on the cardiovascular manifestations due to their significant impact on morbidity and mortality. As such, current understanding of the orthopaedic conditions experienced by these patients is limited. The musculoskeletal implications of more subtle elastic fiber abnormalities, whether due to allelic variants or age-related tissue degeneration, are also not well understood. Recent advances have begun to uncover the effects of elastic fiber deficiency on tendon and ligament biomechanics; future research must further elucidate mechanisms governing the role of elastic fibers in these tissues. Identification of population-based genetic variations in elastic fibers will also be essential. Minoxidil administration, modulation of protein expression with micro-RNA molecules, and direct injection of recombinant elastic fiber precursors have demonstrated promise for therapeutic intervention, but further work is required prior to consideration for orthopaedic clinical application. This review provides an overview of the role of elastic fibers in musculoskeletal tissue, summarizes current knowledge of the orthopaedic manifestations of elastic fiber abnormalities, and identifies opportunities for future investigation and clinical application.

Introduction

Elastic fibers are an essential component of the extracellular matrix of extensible connective tissues.¹ Although they are not the only type of fiber which displays elastic properties, elastic fibers are known for their extreme elasticity and resilience.² Composed of a sheath of fibrillin-based microfibrils surrounding a core of cross-linked elastin,^1,3 the resilient nature of these fibers assists vascular structures, dermis, lung, and musculoskeletal tissue in withstanding repeated cycles of stretch and recoil.^1,2 Elastic fibers are thought to serve an important role in stabilizing collagen fibers and distributing complex multiaxial stresses through the collagen architecture.⁴ The arrangement of elastic fibers is tissue-specific, reflective of each structure’s unique function.¹ Disruptions in the assembly or homeostasis of these fibers can lead to a host of inherited and acquired diseases, ranging in severity from mild alterations in connective tissue plasticity to vascular disorders with life-threatening implications.¹

Historically, the focus of both clinical management and scientific investigation has centered on the cardiovascular manifestations of these diseases due to their significant impact on patient morbidity and mortality.^5–8 Current understanding of the orthopaedic conditions experienced by patients with elastinopathic conditions is limited in both scope and depth. The musculoskeletal implications of more subtle elastic fiber abnormalities, whether due to allelic variants or chronic age-related tissue degeneration, are also not well understood. The purpose of this review is to provide an overview of the role of elastic fibers in the physiology and biomechanics of musculoskeletal tissue, summarize current knowledge of the orthopaedic manifestations of elastic fiber abnormalities, and identify opportunities for future investigation and clinical management.

Assembly and Development

Elastic fibers are formed by the deposition and cross-linking of elastin onto a pre-formed microfibrillar scaffold. The process of elastic fiber assembly involves many intricate details which have been reviewed in depth elsewhere.^9–11 Therefore, only specific features relating to the timeline of elastogenesis in tendons and ligaments are presented here.

The precise timeline of elastic fiber assembly in tendons and ligaments is not well understood, although it seems to occur later in development compared to more elastin-rich tissues that are essential for neonatal survival (e.g., blood vessels).^12,13 While some studies have described the assembly of mature elastic fibers in tendon or ligament during late gestation in cow, horse and rabbit,^13–16 others have reported that this does not take place until postnatal development in mouse, chick, and rabbit.^12,17,18 Much of this apparent contradiction may be attributed to analysis of varying tissues from multiple species, as well as inconsistencies in experimental technique, leading to a range of sensitivities in the measurement or visualization of small quantities of elastic fiber components. A more detailed timeline of elastogenesis was proposed by based on observations in the murine ligamentum flavum,¹⁹ wherein microfibrils, which form the scaffold for elastic fibers, are formed during mid to late gestation (E16-P0), but mature elastic fibers are not assembled until postnatal development (P7-P35). Regardless of when elastogenesis begins, it is clear that expression of most elastic fiber-related proteins decreases dramatically after postnatal development, when the tissue reaches maturity.^13,19 Thereafter, elastic fibers experience little to no turnover after assembly, only undergoing homeostatic maintenance by proteins such as lysyl oxidase-like 1.^20,21 This is possible because the lifetime of elastin is astonishingly long, evidenced by a measured mean carbon residence time of 74 years in human lung, and which is assumed to be similar in other tissues.²² Still, degradation of elastic fibers in tendon and ligament occurs with aging, and these degraded elastic fibers are not generally replaced by newly formed fibers.^16,23–26

Content and Distribution

Excluding the elastin-rich spinal ligaments such as the nuchal ligament and ligamentum flavum, elastin content in tendon and ligament has been reported to range from as low as 0.25% to as high as 10% of the tissue’s dry weight, with various reports of intermediate values.^27–29 Much of the variability in elastin content can be attributed to tissue specialization in order to accomplish specific functional requirements. For example, the equine superficial digital flexor tendon (SDFT) experiences high-strain cyclic loading as it stores and releases mechanical energy during the gait cycle, while the common digital extensor tendon (CDET) serves a more static, positional role.^30,31 Reflecting these established functional requirements, the elastin content in equine SDFT was demonstrated to be 75% greater than the elastin content in the CDET from the same animals.²⁶ Similarly, multiple studies of human and canine tissues have reported greater elastin content in the anterior cruciate ligament (ACL) compared to other tendons and ligaments about the knee.^32–34 In addition to variations between tendons of different functionality taken from the same species, elastin content can also vary within a single type of tendon taken from different species. This phenomenon is exemplified by a 4-fold greater elastin content in human Achilles tendon compared to that in elephant Achilles tendon.³⁵ While differences in gait patterns, activity levels, and other functional parameters explain some of the variation in elastin content between species, other characteristics such as lifespan and tissue size may also be contributing factors.

The largest sub-unit within the hierarchical structure of tendons and ligaments is the fascicle, which is composed of bundles of collagen fibers.³⁶ Elastic fibers within fascicles (i.e., fascicular elastic fibers), are sparsely distributed and aligned with the long axis of the tendon (Figure 1).^37–39 These elastic fibers generally conform to the crimped pattern of the surrounding collagen, although in some cases they appear to take on a more linear morphology.⁴⁰ Less frequently, short and highly branched elastic fibers have also been observed within fascicles.⁴¹ Fascicular elastic fibers are typically colinear with rows of resident tenocytes and appear to make up part of the pericellular matrix (Figure 2).^38,40 Consequently, it has been postulated that the fibrillins which make up the elastic fiber scaffold may bind to cells and serve as a mechanosensor for the tissue.^42–44 In addition to elastic fibers, oxytalan fibers (i.e., bundles of fibrillin-based microfibrils without elastin) are also found in fascicles parallel to the long axis of tendon and ligament.^38,45,46 Due to the similar distribution and composition of oxytalan fibers and elastic fibers, there is likely overlap in their respective functions in mature tissue.

Figure 1.

Elastic fibers (outlined with dashed white lines) are visible interspersed among collagen fibrils in (a) transverse and (b) longitudinal transmission electron micrographs of murine Achilles tendon. The mature elastic fiber structure containing a fibrillin-based microfibrillar scaffold and a stable elastin core is evident. Adapted from Eekhoff et. al.²⁷

Figure 2.

(a) Elastic fibers, fluorescently stained with sulforhodamine B, appear to conform to the collagen crimp pattern and associate with cells in rabbit Achilles tendon. Adapted from Pang et. al.⁴⁰ (b) Elastic fibers in transversely sectioned bovine deep digital flexor tendons imaged using immunohistochemistry. Fascicular elastic fibers, running perpendicular to the imaging plane, appear as punctate specks (white arrow) while more diffuse staining is evident in the interfascicular matrix (yellow arrow). Adapted from Grant et. al.³⁸ (c) Elastic fibers imaged using two-photon excited autofluorescence appear to be straighter than the crimped collagen in porcine superficial digital flexor tendon. (d) A denser mesh-like network of elastic fibers is visible in the interfascicular matrix of a transverse section of porcine long digital extensor tendon.

Fascicles are separated by the interfascicular matrix (IFM). Unlike the sparsely distributed and strongly aligned fascicular elastic fibers, interfascicular elastic fibers form a more dense, mesh-like fiber network that appears to connect adjacent fascicles (Figure 2).^26,38,47 On a larger scale, mesh-like elastic fiber morphology has also been observed between the two bundles of the canine ACL and could perhaps be present in other multi-bundle ligaments or tendons.⁴⁵ Cells residing within the IFM demonstrate a more rounded morphology and are more densely packed than within fascicles. Structural observations of co-localization between cells and the surrounding elastic fibers further reinforces the hypothesis that they may be an important part of the pericellular niche.⁴⁷ Moreover, the elastin-rich IFM may serve a protective role for small blood vessels and nerve fibers which run along the length of the tissue.³⁶

In addition to their relatively high density in the IFM, elastic fibers are also abundant in the peritenon, a sheath of tissue that surrounds each tendon,^37,46,48 as well as the vincular membrane, which anchors some tendons to surrounding structures.⁴⁶ Along with variations in elastin content in tendon-supporting structures, the distribution of elastic fibers may vary even within specific regions of each tendon or ligament. Descriptions of elastic fibers in the enthesis, or tendon-to-bone insertion, are mixed and run the gamut from fewer, to similar, to greater amounts of elastic fibers compared to the tendon midsubstance.^32,46,48 In fibrocartilaginous regions where the tissue experiences compressive forces due to impingement or wrapping around bony structures, elastic fibers are less organized and present in smaller quantities.⁴⁹

Generally, the size of the various sub-units of tendons and ligaments (i.e., fibril, fiber, and fascicle) do not scale with the size of the tissue; rather, the quantity of the subunits changes to allow for differences in cross-sectional area. Within larger tendons, the cross-section of individual fascicles is on the order of 0.1–10 mm². This size is similar to the cross-sectional area of whole tendons from smaller animals (e.g., rodents). Upon close inspection of the structure of mouse and rat tendon, it is apparent that these tendons do not contain the same structure as tendons from humans and other larger species, but instead are structurally similar to a single fascicle, supporting the principle of non-scaling with regard to fascicle size.⁵⁰ This observation is important when investigating elastic fibers because the presence or lack of an elastic fiber-rich IFM may affect how perturbations in elastic fibers influence gross tissue properties. While murine and other small tendons are a convenient and simple model to gain insight into the roles of fascicular elastic fibers, larger models are necessary to fully recapitulate the more complex dual-zoned elastic fiber network present in human tendon and ligament.

Mechanotransduction and Cell Signaling

While there is little information about the impact of elastic fibers on mechanotransduction or cell signaling in tendon or ligament specifically, insights from other tissue will be succinctly presented here because of its relevance for orthopaedic tissue. Fibrillin-1, the main protein of the elastic fiber scaffold, contains an exposed RGD motif which is available for integrin binding on cell surfaces.^51,52 It has been proposed that strain-induced conformational changes to fibrillin-1 could alter the availability of the RGD motif and consequently decrease integrin binding, thereby eliciting a cellular mechanoresponse.^42,43,53 The close proximity between cells and elastic fibers in tendon supports the hypothesis that fibrillin-1 microfibrils may relay mechanical signals to cells in the ECM.^38,40

In addition to playing a role in integrin-mediated mechanotransduction, the fragmentation of elastin through mechanical damage or enzymatic activity may induce a cellular response by the binding of released elastin peptides to elastin receptor complexes.^54,55 Elastin peptides have been demonstrated to induce biological effects such as chemotaxis and protease synthesis on a number of cell types, including fibroblasts.^54,56 While elastin-peptide signaling is known to impact pathologies in the lungs and vasculature, its importance in tendon or ligament is unknown.^57,58

Contribution to Mechanical Properties

Elastic fibers are a significant contributor to the mechanical properties of tendon and ligament. This important role has been established largely through studies utilizing elastase, a proteolytic enzyme which digests elastic fibers. In this experimental scheme, the mechanical contribution of elastin can be elucidated by comparing the mechanical response of tissue before and after elastin degradation. Early work demonstrated a decrease in elastic modulus and increase in hysteresis (i.e., energy loss upon unloading) of human palmaris tendon after elastase treatment.⁵⁹ Other studies did not observe any changes in hysteresis when examining canine ACL, porcine medial collateral ligament (MCL), or rat tail tendon after elastase treatment.^60–62 With regard to failure properties, only rat tail tendon has demonstrated decreased failure stress and strain after elastase treatment. However, the elastase incubation time in this experiment was 3–4 times longer than used for most others, which may have amplified potential off-target effects of the potent protease, thus confounding the results.⁶² In addition to characterizing the tensile properties of tendon and ligament, elastase treatment has been used to examine the role of elastic fibers in shear and transverse tension. For example, human supraspinatus tendon demonstrated decreased stresses in shear loading following elastin degradation.⁶³ Similarly, elastase incubation decreased the mechanical response of porcine MCL in both shear and transverse tension. A greater effect of elastase treatment was observed in these loading configurations compared to tension along the long axis of the ligament, indicating that elastic fibers may link adjacent collagen bundles together to minimize excessive shearing and prevent the bundles from separating with off-axis loading.^61,63

While elastase treatment studies have served a valuable role in establishing the importance of elastic fibers for the mechanical properties of tendon and ligament, this approach does have limitations. First, the proteolytic activity of elastase is not specific to elastin; it can also cleave glycosaminoglycans (GAGs) and minor collagens.^62,64 This may only be a minor limitation since these constituents typically do not play a notable role in the tensile mechanics of tendon and ligament.^65–67 Second, inconsistent treatment protocols and incomplete elastase penetration into differently sized samples makes comparison between studies difficult. Third, current studies have not attempted to distinguish the role of fascicular and interfascicular elastic fibers. This distinction may explain differences in the response between elastase treated human palmaris tendon (which contains both interfascicular and fascicular elastic fibers) and rat tail tendon (which contains only fascicular elastic fibers) reported by Millesi and colleagues.⁵⁹ Further exploration is necessary in this area.

Our research group has recently begun to utilize genetically modified mouse models to investigate the role of elastic fibers in tendon/ligament mechanics. In addition to overcoming the limitations of elastase treatment, these models allow for precise and thorough removal of specific elastic fiber components and enable in vivo studies where the effects of perturbed elastic fibers in living tissue can be examined. Thus far, we have demonstrated a subtle yet significant increase in the stiffness of Achilles tendon and supraspinatus tendon from elastin haploinsufficient mice compared to wild type controls; increased stiffness was associated with a decrease in elastin content of approximately 38%.²⁷ The elastin-deficient tendons in this study did not show any differences with respect to mechanical behavior during stress relaxation. While using mouse models, it should be recognized that murine tendon is structurally similar to a single fascicle from a larger tendon, and therefore the role of the IFM is not accounted for. This may partially explain the increased stiffness in our elastin haploinsufficient mouse model compared to the decreased modulus reported after elastase treatment of larger tendons.⁵⁹ Additionally, the mouse model represents tendon that has undergone development with elastin deficiency, allowing for compensatory changes in the quantity or arrangement of other minor tissue constituents. In contrast, elastase treatment removes elastin from initially healthy tissue.

Due to the differences in the function and elastin content of equine SDFT and CDET, several studies have focused on comparing the properties of these two tendons. Of note, greater fatigue resistance and a lower elastic modulus was seen in the SDFT, which may be due to higher elastin content.^26,68 Although not directly linked to elastin, findings from these studies indicate that mechanical differences between these functionally distinct tendons may also be influenced by variations in the elastin-rich interfascicular matrix.^69,70 These results support the notion that regional specialization between tendon types in response to different loading environments is tied not only to the quantity of elastic fibers, but also their distribution within the tissue.¹⁸

While these studies demonstrate the significant role that elastic fibers play in the mechanical responses of tendon and ligament, the mechanisms by which elastic fibers carry out these functions are not yet understood. Due to the relatively low quantity of elastic fibers in these tissues, it is unlikely that elastic fibers are direct load-bearing structures. Instead, they may act by regulating strain-induced collagen uncrimping and reorganization. For example, an increase in the crimp wavelength of rat tail tendon has been reported following elastase treatment, suggesting that elastic fibers may influence the process of extinguishing collagen crimp patterns with low-strain loading, a phenomenon which is important for tendon extensibility at low mechanical stresses.⁶² Furthermore, strain-induced changes in collagen alignment were greater in elastin haploinsufficient murine Achilles tendon compared to wild-type controls. This indicates that additional tissue reorganization, including collagen fiber sliding and rotation, may be affected by elastic fibers.²⁷ On a larger scale, structural observations suggest that interfascicular elastic fibers may link adjacent fascicles and prohibit interfascicular sliding. If left uninhibited, this process could decrease tissue stiffness and therefore cause joint hyperextensibility and increase the risk of dislocation.^26,38 Continued work will be necessary to fully define how interactions between elastic fibers and the collagen ultrastructure influence tendon and ligament mechanics.

Elastic Fiber Genetic Disorders

Disruptions in the assembly or homeostasis of elastic fibers can lead to a host of inherited and acquired diseases, ranging in severity from mild alterations in connective tissue plasticity to vascular disorders with life-threatening implications.¹ A comprehensive description of all clinical disorders caused by elastic fiber abnormalities is out of the scope of this review; however, the most common conditions – Williams-Beuren Syndrome,^1,5,71,72 cutis laxa,^1,73 Marfan Syndrome,^1,74–77 and Weill-Marchesani Syndrome^1,78,79 – and their relation to musculoskeletal tissues are summarized in Table 1.

Table 1.

Elastic fiber disorders.

Disease	Incidence/Prevalence	Genetic Abnormality	Pathophysiology	Systemic Manifestations	Orthopaedic Manifestations
Williams-Beuren Syndrome	1 in 7,500 (Prevalence)	Sporadic meiotic misalignments	Meiotic misalignments lead to hemizygous deletion or duplication, resulting in elastin haploinsufficiency	Cardiovascular: supravalvular aortic stenosis, peripheral pulmonary aortic stenosis, arterial hypertension, mitral valve disease	Laxity of large joints (may later progress to joint contractures)
		Discrete cluster of genes, including elastin,		Metabolic: glucose intolerance, infantile hypocalcemia	Stiffness of small joints
		chromosome 7q11.23		Dimorphic facial features: medial eyebrow flair, epicanthal folds, upturned nose, elongated philtrum, prominent lips	Large joint dislocations Lordosis Scoliosis
				Short stature
				Intellectual deficits
				Hoarse voice
Cutis Laxa	1–2 in 400,000 (Incidence)	Acquired: destruction of elastic fibers due to inflammatory processes Inherited: autosomal dominant, autosomal recessive, and X-linked; affect a variety of genes involved in structure or assembly of elastic fibers	Alterations in fibulin proteins, intracellular trafficking, amino acid synthesis, TGF-β signaling, elastic fiber synthesis, elastin/collagen deposition	Cardiovascular: aortic aneurysms, aortic root dilatation, pulmonary aortic stenosis, arterial tortuosity Pulmonary: emphysema, diaphragmatic defects Redundant, hypoelastic skin	Generalized joint laxity Congenital hip dislocation Scoliosis
				Craniofacial Macrocephaly Ocular Gastrointestinal abnormalities Hernias
Marfan Syndrome	2–3 in 10,000 (Incidence)	Fibrillin-1 Autosomal dominant (75%) De novo mutation (25%)	Decreased expression, abnormal secretion, altered structure, increased proteolytic susceptibility, altered TGF-β activity	Cardiovascular: aortic dilatation, aortic dissection/rupture, aortic valve prolapse Ocular: superior lens dislocation Dermal: loose skin, striae	Acral dimensions Elongated ribs Pectus excavatum or carinatum
					Hypermobility and joint laxity that may progress to contractures
					Large joint dislocations, patellar subluxation
					Protrusio acetabuli
					Scoliosis, dural ectasia, cervical kyphosis, atlantoaxial translation
					Early-onset osteoarthritis
Weill-Marchesani Syndrome	1 in 100,000 (Prevalence)	Autosomal dominant: fibrillin-1	Abnormal fibrillin-1 leads to altered elastic fiber structure	Cardiovascular: disrupted cardiac development Ocular: lens dislocation, acute and chronic glaucoma, myopia (due to microspherophakic lenses), cataracts	Generalized joint stiffness - predilection for hands
		Autosomal recessive: ADAMTS-10	Abnormal ADAMTS-10 may affect interactions between fibrillin-1 and integrins, and may destabilize TGF-β complexes	Short stature Thickened skin	Trigger digit Compressive neuropathy Brachydactyly

Elastic fiber abnormalities are also seen in hypermobility disorders associated with mutations in genes related to collagen structure or assembly. Tissue biopsies from patients with Ehlers-Danlos syndrome, benign joint hypermobility syndrome, and osteogenesis imperfecta demonstrate fraying, fragmentation, calcification, and disorganization of elastic fibers.^80–82

These diverse, complex disorders involve an array of genetic abnormalities that affect the structure and function of elastic fibers in a variety of ways, creating a broad spectrum of clinical manifestations. Historically, the focus of both clinical management and research has centered on cardiovascular manifestations due to their significant effects on patient survival and overall health.^5–8 However, as the understanding of these disorders has expanded, enhanced management has allowed these patients to live longer and more active lives. Additionally, improved diagnostics have identified milder cases that previously would have gone undetected.⁸³ Despite variations in the clinical spectrum, a common complaint amongst patients with elastic fiber disorders is abnormal joint function, which highlights the integral role that elastic fibers play in the biomechanical properties of periarticular connective tissue structures such as tendons and ligaments. However, the link between elastic fiber abnormalities at the cellular level and the musculoskeletal manifestations in the clinical setting is poorly understood.

Implications for Musculoskeletal Function and Disease

Hypermobility

Joint laxity can be a significant source of pain and disability in patients with hypermobility disorders, where blunted proprioceptive perception can also lead to increased risk of injury.^7,84–87 Once injured, these patients also are also at increased risk of re-injury.⁸⁸ Chronic instability and altered joint biomechanics can lead to abnormal wear patterns and increased stress on articular cartilage, predisposing these patients to development of premature osteoarthritic changes in multiple joints.^89–97 Injuries may involve the upper and lower extremities alike, and can occur along a spectrum ranging from mild recurrent sprains and repetitive low-grade subluxations to frank dislocation events and ligament ruptures. In the lower extremity, these patients may experience medial forefoot collapse, ankle sprains, and ACL ruptures. Upper extremity manifestations may include carpal abnormalities such as increased scaphoid rotation, negative ulnar variance, and increased lunotriquetral motion. Shoulder pathology is also common, presenting as subluxation, dislocation, or multidirectional instability. Patients with multiple dislocations or evidence of instability in multiple joints should undergo further workup for a connective tissue disorder.⁸⁹

Contractures

Contractures may also develop in patients with elastic fiber disorders.^6,8,72 Large joints are typically affected, but involvement of the small joints of the hand have been described as well.⁶ Contractures often develop during childhood; some may remain stable while others will worsen in severity with age.^6,72 Although the impact can be mild for some patients, others struggle with gait abnormalities, general coordination, and simple daily activities such as dressing and feeding. These limitations, along with cosmetic concerns, can have a significant psychosocial impact.⁶

Elastic Fibers and Tendinopathy in the General Population

In tissues where new elastic fiber generation has been evaluated, production tapers sharply in early development and minimal, if any, replenishment occurs thereafter.^22,98 The combination of low turnover rates and the limited machinery available for repair leaves elastic fibers vulnerable to damage and degradation from the biomechanical stresses and resultant inflammation that occurs over an individual’s lifespan.⁹⁹ While the pathogenesis of tendinopathy is multifactorial and has not been fully elucidated, the static state of elastic fibers and their time-dependent degradation could be a contributor to age-related degeneration of tendons. Studies in connective tissues have confirmed that the quantity of functional elastic fibers significantly decreases with age.^23,25 The remaining elastic fibers in aging tendons may demonstrate involution or changes in structure, which inhibits their ability to provide the appropriate recoil and fatigue resistance required for physiologic tendon function.^{22,25,26,98,100–102} Further, elastic fiber content is known to be decreased in cases of chronic tendinopathy, and elastin may be entirely absent from tendons with severe degenerative tendinopathy (Figure 3).¹⁰³

Figure 3.

Histological sections of long head of the biceps tendon biopsies stained with Verhoeff-Van Gieson stain reveal sparse and aligned elastic fibers in samples from healthy patients (a, b) while samples from tendinopathic patients contain regions of dense and disorganized elastic fibers (c) and regions without any elastic fibers (d). Adapted from Wu et. al.¹⁰³

Future Directions

As our understanding of elastic fibers and their important role in the physiologic function of musculoskeletal tissues continues to expand, several important questions remain. First, the link between disrupted elastic fiber homeostasis at the cellular level and the ultimate macroscopic effects on tissue biomechanics and clinical symptoms remains unclear. Second, the development of therapeutic interventions for elastic fiber abnormalities is still in its infancy. These avenues should be further investigated, with a newly directed focus on applications for orthopaedic conditions. Finally, subtle population-wide genetic variations in elastic fiber expression and homeostasis have not been fully characterized.

Several decades ago, Millesi et al. evaluated the effects of elastase and chondroitinase digestion of the palmar aponeurosis in the setting of Dupuytren’s disease.¹⁰⁴ Until recently, minimal further investigation into the clinical effects of elastin deficiency in musculoskeletal tissues were reported. However, in the past few years, several authors have performed sophisticated biomechanical analyses of the Achilles tendon, supraspinatus tendon, and medial collateral ligament of the knee using models of elastin deficiency.^27,29,63,104 These studies provide a foundation for future efforts in understanding the relationship between elastic fiber abnormalities at the microscale and the clinical manifestations that follow. Future studies will benefit from improved experimental models of elastin deficiency; these should include well-designed animal models and improved elastase assays with higher specificity. Further work should also expand to other musculoskeletal structures. Knowledge of the impact of elastic fiber deficiency on tissues essential to joint stability – the cruciate ligaments of the knee, the glenohumeral ligaments, and the capsular tissues of the knee, shoulder, and hip – will be essential to understanding both joint instability and contractures seen in these patients. Additionally, examining the impact of elastic fiber abnormalities on common graft sources for reconstruction and stabilization procedures, such as the medial hamstring tendons, the patellar tendon, and the palmaris longus tendon, could influence surgical management and decision making.

Over the past decade, various genetic and molecular avenues have been described in attempts to modulate the production of elastic fibers. Several studies have reported on the effects of transforming growth factor β1 (TGF-β1) in stimulating the synthesis of elastic fibers. Other authors have explored the possibility of genetic modification utilizing plasmids and adenoviral vectors to produce recombinant elastic fiber molecules in vitro and in vivo.¹⁰⁵ Further still, recent data suggests that elastic fiber production can be increased through changes in post-transcriptional regulation using synthetic micro-RNA molecules.^105–107 Pharmacologic therapy has also shown promise. Several studies demonstrated that the anti-hypertensive medication minoxidil stimulates elastic fiber synthesis, improves function of existing fibers, and decreases fiber degradation.^108–110 These synergistic effects are hypothesized to explain the reversal of age-related arterial changes reported in murine models.¹¹⁰ In addition, direct injection of recombinant tropoelastin has been described in a burn injury model, where it led to formation of new elastic fibers.¹¹¹

Despite these advances, no studies to date have investigated the therapeutic effects of elastic fiber modulation on musculoskeletal tissues. As such, tissue specificity must be explored in greater detail. Additionally, our understanding of the adverse effects of these interventions must be expanded. For example, concerns have been raised regarding the oncogenic potential of TGF-β1 due its broad roles in cell signaling. Adenovirus vectors are highly immunogenic, and therefore can stimulate host responses that may limit efficacy and cause unintended systemic effects. Retroviral vectors exert permanent effects on gene expression once incorporated, which may lead to long-term consequences. Further, incorporation of viral vectors into the host genome takes place exclusively in replicating cells and occurs in a random fashion, which can create unintended mutations.¹⁰⁵

At present, therapeutics with promise for orthopaedic application include minoxidil, micro-RNA, and recombinant protein injections. Minoxidil has an established history of efficacy without significant side effects, even with long-term administration. However, the reported effects on elastic fibers in arteries may be due at least in part to the drug’s systemic vasorelaxant anti-hypertensive properties,¹¹⁰ which would not translate to application in musculoskeletal tissues. While post-transcriptional modulation of elastic fiber production using micro-RNA avoids the concerns related to viral vectors or systemic signaling molecules, altered micro-RNA levels have been associated with fibrosis in the liver, lung, kidney, and heart.¹⁰⁷ Direct injection of recombinant elastic fiber precursor proteins could be easily translated to clinical treatment of orthopaedic ailments and would limit systemic adverse effects. However, this therapeutic model has only been studied in the setting of wound healing, which represents a different biochemical milieu.

Genetic profiles associated with inherited disorders of elastic fibers are well-described, yet variations in gene expression amongst the general population have not been defined. While many acute orthopaedic injuries were previously thought to be caused by extrinsic factors, increasing evidence has emerged to suggest that allelic variations in key genes may influence injury risk. For example, variations in the genes for elastin and fibrillin-2, proteins essential to elastic fiber assembly, have been associated with both Achilles tendinopathy and ACL rupture.¹¹² Use of genetic profiles both for injury risk stratification as well as optimization of physical performance have already been described.^113–117 As the availability, accuracy, and cost of these genetic assessments continues to improve, genetic screening may soon become a routine component of a complete clinical evaluation. Further population-based studies to identify elastic fiber genetic loci associated with increased risk of sustaining an acute injury or developing a degenerative condition will guide prophylactic measures. Such endeavors may help to significantly decrease the morbidity associated with these disorders.

Conclusion

Elastic fibers are an essential component of connective tissues, and disruptions in the assembly or homeostasis of these fibers can lead to a variety of clinical conditions. The orthopaedic manifestations of elastic fiber abnormalities are wide-ranging, and include hypermobility, joint instability, joint contractures, and tendon degeneration. To date, these clinical presentations have received only cursory attention, and our understanding of the underlying pathophysiologic mechanisms is inadequate. Recent advances have begun to uncover the effects of elastic fiber deficiency on the biomechanics of tendons and ligaments,^27,29,63 yet much remains to be discovered. Further research should focus on elucidating these molecular underpinnings as well as identifying population-based genetic variations in elastic fibers. Such information will improve our understanding of how elastic fiber pathology impacts orthopaedic clinical conditions. Ultimately, this may improve clinical management by guiding preventive care, surgical techniques, and novel targeted therapeutic interventions.