Mechanisms of Mucoid Degeneration in the Cruciate Ligament: Role of Denatured Aggrecan Accumulation and Tissue Dysfunction

Introduction

In daily orthopedic practice, magnetic resonance imaging (MRI) scans are routinely performed to investigate knee disorders, and abnormal findings in cruciate ligament (CL) images are frequently encountered. The clinician’s primary concern is whether these abnormal CL findings are the cause of the patient’s current symptoms and require appropriate treatment. Among these abnormalities, the diagnosis of mucoid degeneration of the cruciate ligament (MD-CL) has increased in recent years,^1–4 based on characteristic enlargement and high-signal intensity changes. Accurately estimating the prevalence of MD-CL is difficult due to selection bias across institutions. In a report of over 4000 MRI cases, mucoid degeneration of the anterior CL (MD-ACL) was 1.04% (44/4221),⁵ and mucoid degeneration of the posterior CL (MD-PCL) was 0.154% (20/12972),⁶ indicating that MD-ACL was seven times more common than MD-PCL among active middle-aged adults seeking orthopedic consultation. In contrast, the prevalence of MD-ACL and MD-PCL in cadavers of all ages was 62.3%⁷ and 71%,⁸ respectively, strongly suggesting the presence of asymptomatic MD-CL.

The pathogenesis of MD-CL remains unknown, and various theories have been proposed: traumatic, degenerative, synovial, ectopic, and misrouted stem cell differentiation.^2,9 Recent studies have highlighted the impact of mechanical stress, such as increased tension from posterior tibial tilt¹⁰ and impingement due to a narrow intercondylar notch.¹¹ Various ganglions,^5,6 bone cysts,^5,12 bone erosions,¹³ meniscus injuries,^3,7,12 and knee osteoarthritis (OA)^5,6,8,14,15 have been reported as comorbidities of MD-CL. In clinical practice, it is important to distinguish whether current symptoms are caused by MD-CL or other associated lesions,^1,5,6,14,16 or whether these lesions developed secondarily to MD-CL.¹⁵

Additionally, neuroinflammatory factors may contribute to the development of MD-CL, possibly presenting as pain and limited knee joint range of motion (ROM) during disease progression.⁴ In other words, the presence of MD-CL may not be related to the patient’s current symptoms, which could have been present in the past. Notably, the incidence of MD-CL in patients undergoing total knee replacement is high—MD-ACL at 60.9% and MD-PCL at 69.2%¹⁷—highlighting the importance of recognizing MD-CL as a degenerative condition in older adults.

Histopathologically, MD-ACL and MD-PCL show little difference, but the pathogenesis of MD-CL demonstrates diversity:⁴ (1) MD-PCL is less common than MD-ACL in the active-age group;^5,6 (2) MD-ACL complications are reported frequently in MD-PCL studies (45%⁶–100%¹⁷), whereas MD-PCL complications are rarely reported in MD-ACL studies (0%^2,5,18–12%¹⁹); (3) in older adults, the incidence of MD-ACL and MD-PCL is similar;^7,8,17 (4) bilateral cases have been reported;^20–22 (5) simultaneous MD-ACL and MD-PCL have also been observed.^6,16,17,23 These clinical and epidemiological patterns suggest distinct epigenetic contributing factors for each MD-CL. Furthermore, MD-CL is frequently observed in older adults undergoing knee replacement, likely reflecting age-related degeneration rather than symptomatic disease.

Although many articles have examined mechanical factors and treatment of MD-CL,^2,18 few have explored the underlying etiology and pathogenesis of its diversity. This study investigates the pathogenesis of MD-CL by considering biochemical and physiological factors alongside conventional orthopedic approaches. The goal is to propose appropriate treatment strategies for patients with MD-CL based on its pathophysiology.

Understanding the Intraligamentous Homeostasis

Intraligamentous cellular components include resident fibroblasts known as ligament cells (LCs), ligament stem/progenitor cells (LSPCs),⁹ various immune cells, vascular tissues, lymphatic tissues, nervous tissues, and extracellular matrix (ECM), which consists of collagens, proteoglycans (PGs), noncollagenous proteins, and glycoproteins.^24,25

LCs not only degrade and synthesize ECM but also mediate cell–cell and cell-ECM communication via surface sensors.²⁶ Additionally, LCs secrete cytokines, neuropeptides, and transforming factors through cell surface receptors.²⁷ In essence, LCs are multitasking cells that adapt to mechanical stress using their roles as sensors, receptors, and effectors.

Although ligament tissue turnover is physiologically slow, constant ECM degradation requires continuous replenishment. To support this, a minimal level of tension is necessary for maintaining proper gene translation in the CL.

The ligament has poor vascularity, especially centrally, with limited nutrient vessels to support tissue maintenance,²⁸ contributing to poor healing after trauma. Neurovascular structures are found in the synovial envelope and extend into the interfascicle space via epiligament tissue.^27,29 Lymphatic vessels, responsible for waste transport, share this distribution.^29,30 Sensory nerves and nerve endings are also present within the ligament.²⁵ Various sensory and autonomic nerves within the synovium and epiligament are thought to regulate LC homeostasis through neuropeptides and neurotransmitters.^25,31–35

More than 90% of the ligament ECM is collagen, which provides tensile strength. Collagen’s triple-helical structure has a half-life of 200 years³⁶ and is degraded in vivo by matrix metalloproteinases (MMPs). In contrast, although PGs make up a smaller portion, they play a key role in ligament function. PGs are classified into small leucine-rich PGs (SLRPs: decorin, biglycan, lumican, fibromodulin) and large aggregating PGs (LAPs: aggrecan, versican). In vitro, LAPs have a half-life of about 2 days, and SLRPs over 20 days.^37,38 LAPs are rapidly cleaved due to fast sulfated glycosaminoglycan (sGAG) side chain breakdown. SLRPs degrade more slowly, likely due to their association with type I collagen fibers.³⁷

PG content reflects the “mechanical history” of the ligament: regions under tensile load are rich in versican and decorin, while regions under compression or shear forces are rich in aggrecan and biglycan.³⁹

Among noncollagenous proteins, tenascin-C is a key glycoprotein highly expressed at hard–soft tissue interfaces. Its anti-adhesive properties help fibrocartilage cells resist compression by reducing cell-ECM attachment.²⁴ Tenascin-C expression is a cellular response to compression that contributes to fibrocartilage formation in tendons.⁴⁰

Thus, CL homeostasis is regulated not only by collagen but also by PGs, noncollagenous proteins, glycoproteins, and other ECM components, despite their relatively low abundance.

The Biochemical Components That Reflect the Mucoid Tissues in MD-CL

In MD-CL, typical findings include ligamentous swelling and yellow mass retention observed arthroscopically, yellow substance eruption from the ligament surface incision reflecting elevated intraligamentous pressure, and histological evidence of fascicle swelling and glycosaminoglycan retention with positive Periodic acid-Schiff staining.^4,41,42 These features suggest the accumulation of sGAG chains with water-holding capacity. A biochemical component consistent with these findings is aggrecan, classified as LAP.^38,43 Although versican is more abundant than aggrecan in the CL, its lower sGAG content gives it less water retention capacity, making it less likely to be involved in MD-CL pathogenesis. Aggrecan undergoes rapid turnover and predominantly exists as a degradation product in ligaments.^44,45 Even in normal ligaments, the total aggrecan content reflects a mixture of intact and denatured forms. The sGAG side chains of aggrecan contribute to the pathological characteristics of MD-CL.

To understand MD-CL pathogenesis, three mechanisms must be distinguished: (1) the induction and accumulation of aggrecan, (2) excessive production of denatured aggrecan via proteoglycanase activation, and (3) clearance of denatured aggrecan. Each of these mechanisms should be evaluated independently.

The Influence of the Mechanical Force

Mechanical force is the most influential factor in the LC environment.⁴⁶ Snedeker et al proposed four mechanotransduction pathways through which mechanical stress is transmitted to LCs.²⁶ LCs use these sensory pathways to interpret mechanical stimuli and subsequently secrete proteases to degrade aged ECM and synthesize new ECM accordingly.⁴⁷ These processes are regulated by multiple LC-derived mediators, including cytokines, neuropeptides, transforming factors, growth factors, and transcription factors.^47,48 Ligament remodeling is governed not only by neurogenic inflammatory responses originating from nerve endings but also by autocrine and paracrine signaling from surrounding synovial-derived cells—such as mast cells, fibroblasts, and macrophages.^{27,31–34,49–51}

Enzymes such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and MMPs are upregulated in this process.^39,45,49 Transforming growth factor β (TGF-β), which is elevated during inflammation, plays a dual role by promoting aggrecan synthesis^24,52 and degradation depending on its concentration, thus increasing aggrecan turnover³⁸ and leading to accumulation of intact and denatured aggrecan within the CL.

LCs maintain ECM homeostasis in response to mechanical loading. Tensile stress promotes collagen fiber and SLRP (eg, decorin) synthesis, while compressive stress under hypoxia induces aggrecan production. Mechanical stress activates transcription factors, inducing messenger ribonucleic acid expression for matrix remodeling.⁵³ This is mediated by mechanosensors on fibroblast surfaces, intracellular signaling cascades, nuclear transcription, and extracellular transport of bioactive molecules, which collectively regulate ECM remodeling.²⁶

Under tensile loading, longitudinal LC alignment enhances cell–cell communication and decorin expression, strengthening collagen fiber connections.^54,55 Histologically, increased PG in the interfascicle space may indicate elevated versican and decorin.⁴⁴

Under compression and shear stress, LC mechanosensors like cilia are activated, triggering a shift to a chondrogenic phenotype.^24,28,56 Cells produce pericellular gel-like ECM with aggrecan and a tenascin-C mantle, which buffers pressure from surrounding tissues.^24,40 LCs adopt a rounded morphology, which may be suitable for pressure dispersion and chondroid metaplasia completion.⁵⁷

Impaired Lymphatic Drainage as a Pathological Factor of MD-CL

Physiologically, PG abundance in the central avascular zone of the CL is determined by the balance between PG production and clearance.²⁹ Similarly, linear PG deposition in the interfascicle space likely reflects steady-state deposition, whether due to chondrogenesis or increased PG synthesis by LCs.^54,55 Disruption of this balance contributes to MD-CL pathogenesis.

In healthy CLs, sGAG chain deposition does not exceed physiological levels. MD-CL, however, shows excessive sGAG accumulation. This may result from buildup of intact aggrecan, denatured aggrecan fragments, or free sGAG chains released from aggrecan or versican.

Foreign substance clearance involves macrophage degradation and lymphatic drainage.⁵⁰ In healthy CLs, macrophages are limited to the enveloping synovium and epiligament,⁵⁸ not the ligament proper.⁵⁹ Under pathological conditions, macrophages and other inflammatory cells infiltrate along with neovascularization.^58,60,61 However, macrophage phagocytosis may be insufficient in clearing waste, indicating that lymphatic drainage is the primary mechanism.^29,62

The lymphatic conduit permits drainage of molecules under 70 kD,⁶³ while intact aggrecan is ~250 kD⁶⁴—too large for direct clearance. However, the size of lymphatic vessel fenestrations varies under different physiological and pathological conditions, and these vessels are capable of taking up even high-molecular-weight substances, such as aggrecan, from the interstitium. Steady-state waste clearance depends not only on fenestration size but also on the driving forces of lymphatic flow, including interstitial pressure and contractility. Notably, both mechanisms are impaired under pathological conditions.

Radiologic studies have confirmed the persistence of denatured aggrecan fragments in both healthy and diseased tendons.⁴⁵

In steady-state conditions, sGAG chains (~20 kD) are constantly released from core proteins and can be cleared by lymphatic drainage. Aggrecan core proteins are degraded by MMPs and ADATMTS to fragments small enough for clearance under normal conditions.⁶⁴

In LCs, mechanical stress induces dynamic aggrecan synthesis and degradation, accompanied by neuropeptide-mediated proinflammatory responses that contribute to neurological symptoms, such as pain. Cytokines and neuropeptides stimulate MMPs and ADAMTS to cleave aggrecan, producing denatured fragments. When the rate of aggrecan production and degradation exceeds lymphatic drainage capacity, large gel-like aggregates accumulate within the interfascicle matrix, hindering the release and clearance of sGAG chains.⁴⁹

Even under steady-state conditions, aggrecan is highly susceptible to degradation, leading to the continuous generation of denatured aggrecan within the CL. Denatured aggrecan loses core-protein integrity, and the shortening of sGAG chains exposes numerous negatively charged sulfate and carboxyl groups. These intact and denatured aggrecan molecules undergo electrostatic attraction, hydrogen bonding, and cross-linking interactions, resulting in the formation of large-scale aggregates referred to as “supermolecules.” High local concentrations further promote aggregate enlargement. Moreover, these supermolecules may become electrostatically trapped by ECM components such as collagen, further impairing lymphatic drainage and delaying their clearance from the CL. This mechanism enables the aggregates to persist in a relatively stable state within the CL as MD tissue for extended periods. Over time, long-retained supermolecules may become further stabilized through covalent cross-linking associated with advanced glycation end-products.

During arthroscopic surgery, incision of the MD-CL often results in the extrusion of yellow gelatinous material. This phenomenon indicates that the supermolecules are primarily maintained through water-mediated electrostatic interactions, supporting their characterization as “reversible polymeric supermolecules.” The residual MD tissue remaining within the CL is believed to be more stably anchored through covalent binding with collagen fibers.

Inflammatory cytokines such as interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) can impair lymphatic pumping during acute inflammation.⁶⁵ Impaired lymphatic drainage during inflammation-induced lymphangiogenesis has also been reported in animal models.⁶⁶

Orthopedic Factors Involved in the Pathogenesis of MD-CL

The CL rarely experiences isolated compressive stress; such loading is typically accompanied by local hypoxia. Under combined compression and hypoxia, the CL exhibits enhanced aggrecan turnover because the same stimuli that promote aggrecan synthesis—mediated through canonical TGF-β and hypoxia-inducible factor 1-alpha signaling pathways—also activate proinflammatory cytokines such as IL-1β and TNF-α. These cytokines, in turn, upregulate catabolic enzymes, including ADAMTS and MMPs, through non-canonical pathways.

Consequently, when compressive stress and hypoxia occur simultaneously, both aggrecan synthesis and degradation are accelerated within the CL, resulting in a high-turnover state. However, under these conditions, lymphatic drainage—the primary route for ECM waste clearance in ligaments—is also impaired. As a result, both intact and denatured aggrecan accumulate within the ligament.

Physiological ligament remodeling requires efficient clearance of degraded ECM and its replacement with newly synthesized matrix. However, due to its unique anatomical features, the CL has limited capacity to eliminate waste products through pathways other than lymphatic drainage.

The central regions of the ACL and PCL are poorly vascularized and rely predominantly on diffusion from synovial fluid for nutrient supply. This avascular zone contains sparse lymphatic vessels, resulting in inefficient lymphatic clearance. Thus, it represents a low-nutrient with low-clearance microenvironment. In this setting, hypoxia and poor perfusion do not primarily increase aggrecan synthesis; rather, they lead to the accumulation of denatured aggrecan owing to impaired drainage.

Therefore, MD-CL can be interpreted as a maladaptive degenerative process characterized by the progressive intraligamentous accumulation of intact and degraded aggrecan. This process is driven not only by increased synthesis but also by chronic lymphatic dysfunction in the context of a sustained high-turnover aggrecan state.

On MRI, MD-ACL shows the “celery stalk” sign,⁶⁷ while MD-PCL presents a “tram-track” appearance.⁶ These imaging features reflect the fascicular orientation and the extent of MD changes in each ligament and are useful diagnostic indicators for MD-CL.⁶⁸ Histologically, MD-ACL and MD-PCL differ little, and cases of combined involvement have been reported,^6,16,17,23 suggesting a shared pathological basis. The anatomical and physiological environments of each CL influence the cellular reactivity of LCs and LSPCs, affected by epigenetic factors such as mechanotransduction.⁶⁹

Because compressive and shearing forces—not tensile force—induce aggrecan production via mechanotransduction in LCs,⁷⁰ orthopedic factors were examined for their roles in generating these forces in the CL.

The ACL and PCL are primarily composed of two bundles. Although their kinematic interactions remain debated, twisting between bundles during knee flexion and extension generates intrinsic compressive and shearing forces.²⁹ The ACL’s bundles twist more prominently during flexion, generating these forces.^25,56,71 Additionally, the ACL is prone to impingement in the intercondylar notch during routine flexion.⁷² Increased posterior tibial tilt enhances compressive and shearing between bundles rather than tension, while notch narrowing directly increases compressive stress—shift LC homeostasis toward aggrecan induction. The ACL may also be impinged by the lateral anterior outlet wall during valgus and external tibial rotation.⁷³

In contrast, the PCL’s bundles run more parallel within normal knee ROM, limiting intrinsic compressive and shearing forces.^74,75 PCL stress occurs during hyperflexion—such as sitting on the knees—causing bundle compression and impingement at the femoral intercondylar notch and tibial plateau.^20,29,75,76 Accordingly, MD-PCL often causes pain at terminal flexion.⁴¹

In physically active age groups, the ACL exhibits a higher incidence of mucoid degeneration than the PCL, likely due to its exposure to greater mechanical loads, including compressive and shear stresses during high levels of activity.^5,6 Moreover, the hyperflexion required to induce MD-PCL exceeds that needed for MD-ACL generation, and MD-ACL is often seen as a comorbidity in MD-PCL cases.^6,16 Thus, in active-age groups, MD-CL results from mechanical overproduction of aggrecan.

Mechanical stress increases LC aggrecan synthesis and triggers proinflammatory cytokines and neurogenic inflammation,⁷⁷ resulting in pain and other symptoms. However, asymptomatic MD-CL is increasingly recognized. Contributing factors include slow compensatory aggrecan overproduction, impaired clearance of denatured aggrecan, early or preexisting MD-CL, limited neuroinflammatory response, and age-related neurological decline. In older adults, even without increased aggrecan production, age-related lymphatic dysfunction may lead to gradual denatured aggrecan buildup, explaining the similar prevalence of MD-ACL and MD-PCL in this group.

In some cases, MD-ACL and MD-PCL coexist, where one enlarged ligament impinges the other within the intercondylar notch, generating compressive forces.^78,79 Trauma is frequently associated with MD-ACL. Loganathan et al reported trauma history in 23.1% of MD-ACL cases,⁸⁰ and Pandey et al in 63.6%.² Dennison et al found ACL tears in 38.1% of MD-ACL patients.⁸¹ Trauma and tears may trigger repair responses involving inflammatory cytokines, leading to increased aggrecan turnover and denatured aggrecan accumulation. If turnover exceeds physiological capacity, lymphatic drainage dysfunction may occur, resulting in MD-ACL. Therefore, trauma may act as an initiator of MD-CL.

In MD-ACL, ROM limitation may persist even under anesthesia, suggesting mechanical restriction from the enlarged ligament, possibly with loss of the enveloping synovium.¹² The loss of this synovium is likely secondary to MD-ACL enlargement. However, its disruption deprives the ACL of nutrient and lymphatic supply, contributing further to MD-ACL pathology. The predisposition of the ACL to detachment of its enveloping synovium may partially account for its higher rate of mucoid degeneration relative to the PCL in active-age cohorts.

Conversely, MD-PCL typically does not show ROM limitation under anesthesia,^4,6 suggesting that neuropeptides and neurotransmitters from neurogenic inflammation of the enveloping synovium mediate symptoms. MD-PCL may exist in asymptomatic or symptomatic phases, depending on the presence and extent of neurogenic inflammation. In asymptomatic cases, current PCL changes may reflect prior mechanical stress. In symptomatic cases, compressive and shearing forces likely trigger both pain and worsening of MD-PCL via neurogenic inflammation.⁴

Impacts of Neurovascular and Lymphatic Factors and Aging on MD-CL

In addition to mechanical factors, potential neurovascular involvement must be considered in ligamentous homeostasis, especially in aged individuals.^82–84 Aging leads to a reduction in nutrient vessels due to atherosclerosis and thrombus formation, resulting in chronic hypoxia. Furthermore, lymphatic function is impaired in older adults.^62,85 Age-related biochemical changes in CL include decreased collagen, a marked reduction in PGs and glycoproteins, and accumulation of lipids, ground substance (glycosaminoglycans), and calcium deposits.^82,86 The number of LSPCs also declines with age,⁸⁷ reducing their self-renewal and differentiation capabilities.⁸⁸ Additionally, the activity of MMP in tenocytes increases with age.⁸⁹

MD-CL pathogenesis may involve metabolic disorders due to hypoxia caused by increased intratendinous hydrostatic pressure from twisted bundles. Hypoxia induces the expression of cytokines and proinflammatory molecules, including platelet-derived growth factor, IL-6, IL-8, vascular endothelial growth factor, and hypoxia inducible factor 1 alpha, which affect MMP production in fibroblasts.^90–92 Hypoxia can trigger chondrogenic metamorphosis and MD changes via denatured aggrecan overproduction with MMP activation.⁹³ Inoue suggested thrombus formation in nutrient vessels may contribute to MD-PCL development,⁴ and cytokines are known to promote thrombosis.⁹⁴ The high incidence of MD-CL in older adults may be due to age-related degeneration of nutrient and lymphatic vessels, increased expression of MMPs and ADAMTS, and elevated levels of proinflammatory cytokines like TNF-α and IL-1β in aged fibroblasts, all contributing to denatured aggrecan production.^{62,86,95–97}

Neuropeptides, once thought to be produced exclusively by neurons, are now known to be synthesized by tenocytes.⁹⁸ Neuropeptides from stimulated cells or nerve endings modulate matrix turnover.⁴⁹ For example, substance P and calcitonin gene-related peptide indirectly regulate MMP-1 and MMP-3 expression, in addition to mediating pain.⁴⁹ Ackermann et al described three major neuronal signaling pathways in tendons: autonomic, sensory, and glutamatergic.³¹ Neuropeptides promote cell proliferation, angiogenesis, and stem cell stimulation in vitro, aiding tendon healing.³³ In older adults, the number of nerve endings decreases,⁹⁹ conduction velocity in unmyelinated axons slows,¹⁰⁰ and cerebrospinal diseases may contribute to ligament degeneration.³²

Exogenous nerve growth factor promotes ligament healing through collagen synthesis, stimulates neuropeptide production via neuronal sprouting, and enhances angiogenesis.¹⁰¹ Thus, nerves and vessels form neurovascular bundles, which maintain ligament homeostasis in coordination with lymphatics as the excretory system. Martins et al reported a correlation between degeneration of the PCL synovial neurovascular bundle and PCL degeneration.¹⁰² Because this bundle enters the knee via the posterior oblique popliteal ligament, nerves and vessels may be susceptible to impingement at this site.¹⁰³ Indeed, MD-PCL has been reported in individuals working in kneeling or sitting-on-knee positions.²⁰

Recommendations for Treatment Strategies from the Perspective of MD-CL Pathophysiology

The duration and intensity of mechanotransduction dictate aggrecan production, while lymphatic drainage dysfunction defines MD-CL pathogenesis. That intraligamentous pressure reduction via debulking surgery improves MD-CL—despite persistent mechanical anatomy—suggests impaired intraligamentous circulation is a core mechanism.^4,21 Before the complete degeneration of nutrient and lymphatic systems, pressure reduction may restore circulation,¹⁰⁴ reduce denatured aggrecan production, and enable its gradual excretion, thus resolving MD changes. While the threshold at which regeneration becomes irreversible requires further study, it is plausible that fibroblast recruitment and vascular or lymphatic ingrowth from the enveloping synovium may regenerate circulation within the ligament.

During surgery, a longitudinal split is recommended to preserve the enveloping synovium and epiligament circulation,⁵⁸ promoting revascularization and lymphangiogenesis into the ligament.^41,105 Because MD-CL is nonneoplastic, complete resection is unnecessary. Radiofrequency ablation of the degenerated region has also been described.^105,106 If intercondylar notch narrowing is morphologically evident, combined notch plasty may be warranted.

Bone cysts and erosions often accompany MD-CL,¹³ indicating increased collagenase activity (eg, cathepsin K and tartrate-resistant acid phosphatase) in the enveloping synovium,¹⁰⁷ which may lead to collagen fiber degeneration and future ligament rupture. Early debulking in such cases reduces synovial inflammation and improves intraligamentous circulation. Surgery is necessary for any comorbid conditions contributing to symptoms (eg, meniscal injuries). However, surgery for bone cysts is typically unnecessary, as cysts often resolve once synovial inflammation subsides.¹³

As conservative treatment, flexion-limiting orthoses may reduce compressive and shearing forces on the CL. This may alleviate neurogenic inflammation and reduce aggrecan production, enhancing lymphatic drainage and reducing excretory burden. Levy et al and Lintz et al reported a bimodal age distribution of MD-ACL, occurring in both younger and older individuals.^8,12 This pattern suggests that reduced mechanical stress and physical activity with aging might temporarily improve MD-ACL. However, prolonged exposure to MD-CL conditions can alter ligament viscoelasticity, potentially promoting osteoarthritis development. Therefore, careful monitoring during conservative treatment is essential.¹⁵

Future Prospects and Supplementary Notes

The presence of asymptomatic MD-CL indicates a form of MD-CL that does not involve neurogenic inflammation. This may result from aggrecan production exceeding physiological levels, without effective lymphatic excretion. This may also involve intact and denatured aggrecan forming relatively stable “supermolecules” that become difficult to expel outside the ligament even in the steady-state.

In cases of gradual aggregation, neuropeptides are less involved, resulting in asymptomatic MD-CL. In other words, noninflammatory MD-CL may represent the asymptomatic variant.

Unilateral neural input activates the contralateral nervous system at the spinal cord level,¹⁰⁸ suggesting that neurotransmitter and neuropeptide production in unilateral MD-CL could affect the contralateral CL via spinal cord synapses.^31,108,109

The incidence of MD-CL in older adults reaches 60%–70%,^7,8,17 and MD-CL should be viewed as a component of whole-joint knee arthrosis. Viscoelastic changes in the ligament due to MD-CL may lead to knee OA^15,17 and secondary lesions such as meniscus injury,² requiring treatment tailored to the patient’s condition.

Beyond mechanotransduction, neural and vascular factors may contribute to MD-CL pathogenesis. Ethically, it is not feasible to excise an entire CL with surrounding tissues as a single in vivo specimen to study its vascular and neural connections. Moreover, due to species-specific anatomical and neurogenic differences, findings from animal models cannot be directly applied to humans. Thus, human studies using fresh, unfixed specimens with MRI-confirmed MD-CL are essential to elucidate its true pathogenesis.

Finally, PG is a vital substance for living organisms and a physiologically essential biomaterial in the CL. Although this paper focuses on degenerative diseases caused by PG accumulation, PG should also be recognized as a “positive cofactor,” serving as a scaffold for new tissue regeneration. A physiological PG level is essential for maintaining CL function. If our biochemical hypothesis proves valid, it could carry significant clinical and research implications.

Conclusion

MD-CL is a pathological condition caused by an imbalance between the production of denatured aggrecan and its efflux from the ligament, with impaired matrix turnover or interstitial fluid drainage possibly contributing to its accumulation. In active-age groups, MD-CL is induced by mechanotransduction pathways involving neuropeptides. In older adults, age-related lymphatic drainage dysfunction reduces denatured aggrecan excretion. Both presentations involve abnormal denatured aggrecan accumulation within the ligament matrix. This deposition impairs CL integrity, alters viscoelasticity, and may possibly lead to OA and meniscus damage.