Occurrence of Tendon Pathologies in Metabolic Disorders
This article reviews the pathogenetic role of metabolic disorders, which are of paramount relevance to the progression of tendon damage. In diabetes, the prevalence of rheumatological diseases is high, mainly because of the deleterious effects of advanced glycation end products that deteriorate the biological and mechanical functions of tendons and ligaments. In heterozygous familial hypercholesterolaemia, most patients develop Achilles xanthomatosis, a marker of high risk for cardiovascular disease caused by cholesterol deposition in the tendons. Tendon degeneration has also been observed in non-familial hypercholesterolaemia. Monosodium urate crystal deposition in soft tissues is a hallmark of chronic gouty arthritis. In this group of diseases, the mobilization of cholesterol and uric acid crystals is presumably followed by low-grade inflammation, which is responsible for tendon degeneration. Adiposity may contribute to tendon disorders via two different mechanisms: increased weight on the load-bearing tendons and systemic dysmetabolic factors that trigger subclinical persistent inflammation. Finally, tendon abnormalities have been observed in some rare congenital metabolism disorders such as alkaptonuria.
Progress in research has increased our understanding of tendon physiology and the pathogenetic pathways of chronic tendinopathies. Trans-membrane proteins called integrins connect the extracellular collagen fibrils to the cytoskeleton of tenocytes. Under normal exercise conditions, fibril stretching activates subcellular biology, releasing growth factors and triggering the subsequent synthesis of extracellular matrix components, predominantly proteoglycans and collagen neofibrils. Homeostasis is maintained by the simultaneous production of appropriate metalloproteinases (MMPs), which counteracts the anabolic effects of growth factors. When fibril stretching is increased but remains within the physiological window, synthesis prevails over degradation and tendon hypertrophy occurs. However, when repeated loading deviates from normal limits by differences in magnitude, frequency, duration and/or direction, overuse injury may develop. An aberration in proteoglycan metabolism is likely to drive the pathogenesis of tendon damage, as excess proteoglycan production leads to water retention and pressure from swelling. The biochemical adaptation to these changes involves the production of pro-inflammatory agents such as IL-1 β, TNF-α and prostaglandins (PG). Some of the detrimental effects of these pro-inflammatory cytokines include enhanced production of MMPs that cause matrix destruction.
The following pathogenetic cascade is very complex and involves tenocyte apoptosis, hypoxia, neovessel proliferation, smoldering disorganized fibrillogenesis, collagen fibre disruption and hyaline and mucoid degeneration, usually with an absence of inflammation in the advanced stages.
Of note, the progression of the disease is characterized by substantial individual differences. Indeed, tendon integrity is disrupted at comparably high loads only in some individuals, and in a small subset of individuals, exposed to such environmental chemicals as fluoroquinolone antibiotics and statins, tendon integrity disruption can occur even within a normal mechanical load range. Intrinsic and extrinsic factors, including genetics, age, drugs, hormones and blood supply, influence the biological milieu and tendon adaptation to mechanical loading.
In this context, the role of metabolic factors is of paramount importance. Clinical and experimental research shows that diabetes, obesity and, to a lesser extent, hypercholesterolaemia, hyperuricaemia and some rare congenital metabolism disorders (alkaptonuria, glucose-6-phosphatase deficiency and hypergalactosaemia) are frequently associated with tendon degeneration, thus influencing the mechanical properties of tendons and even impairing the healing process after surgery. The aim of this review is to summarize the present knowledge on this topic and to analyse the mechanisms for the negative effects of these metabolic disorders.
A search of English language articles was performed in PubMed, Web of Knowledge (WOK) and EMBASE using the key search terms tendinopathy or tendon, combined with obesity, diabetes, hypercholesterolaemia, hyperuricaemia, alkaptonuria, glucose-6-phosphatase or hypergalactosaemia, independently. Bibliographies were hand searched to include any applicable studies that were not captured by our search. Articles were eligible if they provided specific information related to the correlation between tendon disease and metabolic disorders.
Abstract and Introduction
Abstract
This article reviews the pathogenetic role of metabolic disorders, which are of paramount relevance to the progression of tendon damage. In diabetes, the prevalence of rheumatological diseases is high, mainly because of the deleterious effects of advanced glycation end products that deteriorate the biological and mechanical functions of tendons and ligaments. In heterozygous familial hypercholesterolaemia, most patients develop Achilles xanthomatosis, a marker of high risk for cardiovascular disease caused by cholesterol deposition in the tendons. Tendon degeneration has also been observed in non-familial hypercholesterolaemia. Monosodium urate crystal deposition in soft tissues is a hallmark of chronic gouty arthritis. In this group of diseases, the mobilization of cholesterol and uric acid crystals is presumably followed by low-grade inflammation, which is responsible for tendon degeneration. Adiposity may contribute to tendon disorders via two different mechanisms: increased weight on the load-bearing tendons and systemic dysmetabolic factors that trigger subclinical persistent inflammation. Finally, tendon abnormalities have been observed in some rare congenital metabolism disorders such as alkaptonuria.
Introduction
Progress in research has increased our understanding of tendon physiology and the pathogenetic pathways of chronic tendinopathies. Trans-membrane proteins called integrins connect the extracellular collagen fibrils to the cytoskeleton of tenocytes. Under normal exercise conditions, fibril stretching activates subcellular biology, releasing growth factors and triggering the subsequent synthesis of extracellular matrix components, predominantly proteoglycans and collagen neofibrils. Homeostasis is maintained by the simultaneous production of appropriate metalloproteinases (MMPs), which counteracts the anabolic effects of growth factors. When fibril stretching is increased but remains within the physiological window, synthesis prevails over degradation and tendon hypertrophy occurs. However, when repeated loading deviates from normal limits by differences in magnitude, frequency, duration and/or direction, overuse injury may develop. An aberration in proteoglycan metabolism is likely to drive the pathogenesis of tendon damage, as excess proteoglycan production leads to water retention and pressure from swelling. The biochemical adaptation to these changes involves the production of pro-inflammatory agents such as IL-1 β, TNF-α and prostaglandins (PG). Some of the detrimental effects of these pro-inflammatory cytokines include enhanced production of MMPs that cause matrix destruction.
The following pathogenetic cascade is very complex and involves tenocyte apoptosis, hypoxia, neovessel proliferation, smoldering disorganized fibrillogenesis, collagen fibre disruption and hyaline and mucoid degeneration, usually with an absence of inflammation in the advanced stages.
Of note, the progression of the disease is characterized by substantial individual differences. Indeed, tendon integrity is disrupted at comparably high loads only in some individuals, and in a small subset of individuals, exposed to such environmental chemicals as fluoroquinolone antibiotics and statins, tendon integrity disruption can occur even within a normal mechanical load range. Intrinsic and extrinsic factors, including genetics, age, drugs, hormones and blood supply, influence the biological milieu and tendon adaptation to mechanical loading.
In this context, the role of metabolic factors is of paramount importance. Clinical and experimental research shows that diabetes, obesity and, to a lesser extent, hypercholesterolaemia, hyperuricaemia and some rare congenital metabolism disorders (alkaptonuria, glucose-6-phosphatase deficiency and hypergalactosaemia) are frequently associated with tendon degeneration, thus influencing the mechanical properties of tendons and even impairing the healing process after surgery. The aim of this review is to summarize the present knowledge on this topic and to analyse the mechanisms for the negative effects of these metabolic disorders.
A search of English language articles was performed in PubMed, Web of Knowledge (WOK) and EMBASE using the key search terms tendinopathy or tendon, combined with obesity, diabetes, hypercholesterolaemia, hyperuricaemia, alkaptonuria, glucose-6-phosphatase or hypergalactosaemia, independently. Bibliographies were hand searched to include any applicable studies that were not captured by our search. Articles were eligible if they provided specific information related to the correlation between tendon disease and metabolic disorders.