The intrinsic pathogenetic mechanisms of tendinopathies are largely unknown and whether inflammation or degeneration has the prominent role is still a matter of debate. Assuming that there is a continuum from physiology to pathology, overuse may be considered as the initial disease factor; in this context, microruptures of tendon fibers occur and several molecules are expressed, some of which promote the healing process, while others, including inflammatory cytokines, act as disease mediators. Neural in-growth that accompanies the neovessels explains the occurrence of pain and triggers neurogenic-mediated inflammation. It is conceivable that inflammation and degeneration are not mutually exclusive, but work together in the pathogenesis of tendinopathies. IntroductionPrimary disorders of tendons are common and account for a high proportion of referrals to rheumatologists and orthopedic surgeons [1]. The most commonly involved tendons are the rotator cuff (particularly supraspinatus) and biceps brachii tendons in the shoulder, the forearm extensor and flexor tendons in the forearm, the patella tendon in the knee, the Achilles tendon in the lower leg, and the tibialis posterior tendon in the ankle and foot.Historically, the term tendinitis was used to describe chronic pain referring to a symptomatic tendon, thus implying inflammation as a central pathological process. However, traditional treatment modalities aimed at modulating inflammation have limited success [2] and histological studies of surgical specimens consistently show the presence of degenerative lesions, with either absent or minimal inflammation [3,4]. As will be clear in this review, we favor the hypothesis that inflammation and degenerative changes often coexist in the course of tendon disorders, and their relative contributions are difficult to dissect. Therefore, the definition of 'tendinitis' has been largely abandoned and the terms 'tendinosis' or, more generically, 'tendinopathy' (TP) are now currently preferred [5].In this review we summarize recent findings useful for understanding the pathogenesis of primary tendon diseases. First, suggestions coming from epidemiology, histopathology and clinics are reported, then we discuss new data on biochemical changes that occur in experimental and human TPs. Finally, we propose a unifying theory, drawn from both experimental and clinical data. Anatomy and physiologyThe tendons are made up of bundles of collagen fibrils (primary, secondary and tertiary fibers), each wrapped in endotenon, which in turn is enveloped by an epitenon, forming the actual tendon. A true synovial sheath is present only in some tendons, such as tibialis posterior, peroneal, and extensor and flexor tendons of the wrist and the hand; other

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.

Platelet-rich plasma (PRP) has recently become the focus of intensive interest and discussion, in part because of the expanding understanding of platelet function. Anucleate platelets within PRP release a myriad of growth factors and cytokines while contributing to plasma coagulation and fibrin development; the latter acts as vehicle for the local delivery. The biological effects of PRP are largely attributed to the platelet secretome and plasma signaling proteins. Clinical data suggest that PRPs may exploit different regenerative mechanisms under diverse disease conditions, including hemostasis, inflammation, angiogenesis and the synthesis of extracellular matrix. The success of PRP therapies depends on current tissue healing research and the translation of this knowledge into clinical developments.

Several rheumatologic manifestations are more pronounced in subjects with diabetes, ie, frozen shoulder, rotator cuff tears, Dupuytren’s contracture, trigger finger, cheiroarthropathy in the upper limb, and Achilles tendinopathy and plantar fasciitis in the lower limb. These conditions can limit the range of motion of the affected joint, thereby impairing function and ability to perform activities of daily living. This review provides a short description of diabetes-related joint diseases, the specific pathogenetic mechanisms involved, and the role of inflammation, overuse, and genetics, each of which activates a complex sequence of biochemical alterations. Diabetes is a causative factor in tendon diseases and amplifies the damage induced by other agents as well. According to an accepted hypothesis, damaged joint tissue in diabetes is caused by an excess of advanced glycation end products, which forms covalent cross-links within collagen fibers and alters their structure and function. Moreover, they interact with a variety of cell surface receptors, activating a number of effects, including pro-oxidant and proinflammatory events. Adiposity and advanced age, commonly associated with type 2 diabetes mellitus, are further pathogenetic factors. Prevention and strict control of this metabolic disorder is essential, because it has been demonstrated that limited joint motion is related to duration of the disease and hyperglycemia. Several treatments are used in clinical practice, but their mechanisms of action are not completely understood, and their efficacy is also debated.