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UNDERSTANDING TENDINOPATHIES OF THE HIP & PELVIS BOOK ONE: Mechanobiological mechanisms and implications for understanding aetiology and management of tendinopathy Introduction Tendinopathies of the hip and pelvis represent a large burden on both the sporting and ageing populations. Growing evidence is shaping contemporary conservative management of tendinopathy.

This e-book series aims to provide readers with guidance towards a deeper understanding of tendinopathies of the hip and pelvis and more effective clinical management based on an emerging evidence base derived from scientific studies on structure and mechanobiological mechanisms, risk factors, impairments and the available information on effects of intervention.

This first book dives deep into the mechanobiological mechanisms associated with tendinopathy. First, an understanding of basic tendon structure is required before introducing the molecules that maintain homeostasis and exploring the influence of cytokines and mechanical loading. With this knowledge in hand, aetiological models of tendinopathy, stages of tendinopathy, pain mechanisms and other factors that may predispose to tendinopathy are considered. An understanding of proposed mechanobiological mechanisms underlying the development of tendinopathy underpins the development of appropriate management strategies that will be discussed for each region in subsequent books.

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This book is suitable for anyone involved For more information in management of tendinopathies of the hip and pelvis or prescription of email [email protected] exercise in at-risk groups – such as the phone (07) 3342 4284 athletic population or perimenopausal web dralisongrimaldi.com women. The content assumes readers have a basic knowledge of anatomy and muscle function in this region.

PAGE 2 OF 36 Copyright Alison Grimaldi 2018 BOOK CONTENTS

Chapter 1 BASIC TENDON STRUCTURE...... 4

Chapter 2 MOLECULES MAINTAINING HOMEOSTASIS...... 8

Chapter 3 THE INFLUENCE OF MECHANICAL LOADING...... 11

Chapter 4 THE ROLE OF INFLAMMATION...... 14

Chapter 5 MODELS OF TENDINOPATHY...... 16

Chapter 6 THE PAIN OF TENDINOPATHY...... 21

Chapter 7 OTHER RISK FACTORS ...... 25

SUMMARY & CONCLUSION...... 30

REFERENCE LIST...... 32

TENDON CELLS Tenocytes

EXTRACELLULAR MATRIX Collagen fibres Proteoglycan molecules

PAGE 4 OF 36 Copyright Alison Grimaldi 2018 Basic Tendon Structure

Basic tendon structure consists of tendon Proteoglycans are molecules that consist of a cells or tenocytes (a type of fibroblast) and the core protein and one or more glycosaminoglycan extracellular framework or matrix which includes (GAG) chains. In general, proteoglycans fill the collagen fibres and proteoglycan molecules gaps between the collagen fibres and tenocytes, (Figure 1). Tenocytes produce the extracellular serving to assist in assembling collagen fibres, matrix for human tendon tissue and release maintaining form and providing lubrication for many other signalling molecules that may have fibres sliding against one another. an endogenous effect on the tenocyte that released it, the neighbouring tenocytes or even Proteoglycans can be divided into small and cells distant from the region. Tenocytes are able large molecules with differing functions (Table to pass messages via a series of gap junctions 1). While tenocytes deposit collagen segments between cells. This process is reviewed in an into the extracellular matrix, small proteoglycans excellent article by Khan & Scott 2009. assemble the pieces and ensure perfect alignment for optimal strength. Decorin, which Within the extracellular matrix, the collagen is the most abundant proteoglycan, is thought fibres provide the structure for the tendon and to be primarily responsible for modulating the allow transmission of load between the formation and final sizes of the collagen fibrils. muscle and bone of attachment. Collagen fibrils Biglycan and fibromodulin provide the niche for are arranged in tightly packed bundles, for the tendon stem cells which produce new tenocytes. most part arranged longitudinally along the These small proteoglycan niches can be thought tendon. There are relatively few fibres crossing of as nurseries for new tendon cells. the tendon, to providing resistance against transverse forces.

Gap junction

ECM

Tenocytes Proteoglycans Produce ECM Assemble collagen fibres Produce signalling molecules Collagen Fibres Maintain form Derived from stem cells Structure Lubricant

Figure 1: Structure of a tendon; ECM = Extracellular Matrix

Examples Decorin, Biglycan, Fibromodulin Aggrecan, Versican, Lumican

Water binding Actions Assemble & align collagen fibres Maintain form Niche for tendon stem cells Resist compression

Location More prevalent in tensile zone Transition and compressive zones

Hosaka et al 2005, Magnussen et all 2010, Hart & Scott 2012

Table 1: Types, function and locations of proteoglycans within tendons

The large proteoglycans, aggrecan, versican and Fibrocartilage has a low fluid permeability due lumican are negatively charged, water attracting to trapping of water by proteoglycans, making it molecules. They bind water, helping to maintain much more suited to compressive loading but form, particularly against compressive loading. not well suited to tensile loading. Aggrecan is the major proteoglycan present in This compressive zone is usually protected from cartilage, a structure which undergoes regular tensile loads by wrapping around a bone prior to cyclic compression. Within tendon, the different insertion. This bony cam prior to insertion has types of proteoglycans have a site-specific also been suggested to provide a mechanical prevalence depending on the requirements of advantage for the tendon, providing a pulley- each tendon zone. like effect.

Each tendon has three major zones – the tensile Proteoglycan distribution is consistent with zone, the transition zone and the compressive the needs of the relevant zones (Figure 2). Large zone (Figure 2). The tensile zone is the area proteoglycan molecules such as aggrecan are distant from the bony insertion. It is made predominantly found in tendon compressive up of fibrous collagen tissue with high fluid and transition zones. These large proteoglycans permeability. It is optimally designed, as its name can attract and retain water up to 50 times suggests, to absorb longitudinal, tensile loads. their weight, a very helpful defence against The transition and compressive zones occur compressive loading. Conversely, in the tensile at the bony insertion of the tendon, termed the zone, smaller proteoglycans such as decorin enthesis organ (Benjamin et al 2004). Fibrous tissue and bigylcan are predominant. is gradually replaced through the transition zone, deep surfaces first, by unmineralised fibrocartilage, and then by calcified fibrocartilage at the bony interface.

PAGE 6 OF 36 Copyright Alison Grimaldi 2018 TENSILE ZONE COMPRESSIVE ZONE Fibrous tissue Fibrocartilage High fluid permeability Adjacent to bone Less suited to Low fluid permeability compression Less suited to tension Higher % smaller TRANSITION Higher % larger ZONE proteoglycans proteogycans

Bursa

Unmineralised fibrocartilage

Calcified fibrocartilage

Figure 2: Zones of a tendon

ENZYMES Matrix metalloproteinases Tissue Inhibitors of MMPs

CYTOKINES Pro-catabolic Pro-anabolic

PAGE 8 OF 36 Copyright Alison Grimaldi 2018 Enzymes Cytokines

Homeostasis of tendon Cytokines are cell to cell structure requires a balance messenger molecules which of intrinsic enzymatic play an important role in processes. tendon homeostasis.

In a normal healthy tendon, tenocytes produce Cytokines are produced by cells such as the extracellular matrix and the breakdown tenocytes and immune cells, and impart their of matrix constituents is performed by effect either by release into the circulation or enzymes called matrix metalloproteinases or by direct release into tissues. With respect to MMP’s. These enzymes are released from the tendon health, there are two major types of tenocytes themselves and also from activated cytokines, those that have a pro-anabolic, or inflammatory cells such as macrophages. There building up effect and those that have a pro- are a number of different MMP’s that breakdown catabolic, or breaking down effect (Table 2). different parts of the matrix - MMP 1,8, and 13 for example are important in cleaving and Pro-anabolic cytokines include a variety of breaking up the large Type 1 collagen fibres. growth and differentiation factors, that stimulate This is a normal part of maintenance, however cell proliferation and regulate the synthesis of the action of MMP’s must be tightly controlled extra-cellular matrix components and expression to avoid excessive matrix destruction. of collagen Type I and collagen Type III. These cytokines aid in production of collagen while The role of TIMP’s, tissue inhibitors of inhibiting the effect of MMP’s by stimulating metalloproteinases, is to inhibit the action of release of TIMP’s. However, balance is crucial - MMP’s. Imbalance in MMP’s and TIMP’s can overexpression of TGFβ, a pro-anabolic cytokine, result in malignancy, cardiovascular disease, results in tissue fibrosis. autoimmune disease and inflammatory disorders. Similarly, such an imbalance may result in excessive destruction of the tendon matrix. This process will be influenced by a number of cytokines.

MMPs TIMPs PRO-CATABOLIC PRO-ANABOLIC CYTOKINES = CYTOKINES Matrix Destruction Inhibit MMPs

HOMEOSTASIS

Figure 3: Enzyme and cytokine balance required for tendon homeostasis

Pro-catabolic cytokines, often referred to as pro-inflammatory cytokines, include tumour necrosis factor (TNF) alpha and members of the interleukin family. These cytokines will stimulate release of MMPs from macrophages and tenocytes resulting in collagen breakdown. They have also been implicated in apoptosis, the stimulation of pre-programmed death of tenocytes. Expression of TNF alpha has been shown to be increased in pathological tendons (Hosaka et al 2005).

Pro-catabolic Cytokines Pro-anabolic Cytokines

Examples TNFα (Tumour Necrosis Factor Alpha) Growth factors IL-1 (Interleukin -1) TGFβ (Transforming Growth Factor Beta) IGF-1 (Insulin like Growth factor) CTGF (Connective Tissue Growth Factor)

Actions Stimulate release of MMP’s Cell proliferation Collagen breakdown Stimulate collagen production Apoptosis – tenocyte death Stimulate release of TIMP’s

Cytokines are released by many cells, including tenocytes & immune cells such as Origins macrophages & lymphocytes

Table 2: Types, actions and origins of cytokines that influence tendon health and structure

(Hosaka et al 2005), Magnussen et al 2010, Hart & Scott 2012

PAGE 10 OF 36 Copyright Alison Grimaldi 2018 CHAPTER THREE THE INFLUENCE OF MECHANICAL LOADING

MAGNITUDE & FREQUENCY OF LOADING

TYPE OF LOADING Tension Compression

Copyright Alison Grimaldi 2018 PAGE 11 OF 36 Magnitude & frequency of mechanical loading If however, the loading is greater than that to which the tendon can adapt, catabolic processes In a situation of regular positive loading will outweigh anabolic processes resulting in there will be homeostasis, where anabolic matrix degradation. Influencing factors may and catabolic processes are in balance. Hart include type of loading, amount of loading, how and This physiological window is thought quickly the loading was increased and how to be highly individual and determined by much rest was instituted between loading. In many factors including genetics, age, sex, the first 24-36hours after loading there is a net lifetime loading history, presence of prior degradation of collagen. Applying high loads injury or scar tissue, systemic factors such as again within this window may result in damage diabetes and obesity, lifestyle factors such as (see Magnussen et al 2010 for review). smoking and nutrition and local anatomy and biomechanics (Hart & Scott 2012). The optimal In true reflection of the ‘use it or lose it principle’, amount of loading or physiological window if loading is reduced significantly, the tendon will therefore be different for each individual. will adapt by weakening. Researchers have reported an increase in MMP-13 expression Mechanical loading has been shown associated with collagen stress deprivation to create both anabolic and catabolic (Thornton et al 2010). MMP-13 is very active in effects, but gradual increments of load, breakdown of large Type I collagen fibres. A appropriately spaced will result in a net reduction in Type 1 collagen fibres will result positive effect with an increase in pro- in reduced load tolerance of the tendon. This anabolic cytokines and increased collagen is consistent with earlier findings that stress synthesis and turnover (Figure 4). deprived tendon tissue fails at relatively lower strain rates (Yamamoto et al 1999). The window of tendon homeostasis is highly individual

STRESS HOMEOSTASIS: POSITIVE FAILURE TO DEPRIVATION: ADAPTATION: ADAPT:

CATABOLISM ANABOLISM ANABOLISM CATABOLISM > = > > ANABOLISM CATABOLISM CATABOLISM ANABOLISM

Increase in MMPs Increase in anabolic Increase in MMP’s & catabolic cytokines, collagen & catabolic cytokines synthesis & turnover cytokines

< Normal Regular LOAD >Normal >>Normal

Figure 4: Effect of mechanical load on biological processes within a tendon

PAGE 12 OF 36 Copyright Alison Grimaldi 2018 Type of mechanical loading

Type of loading will also have a significant as calcific spurs at the tendon origin. As with influence on tendon mechanobiological stress shielding, research has demonstrated that processes. The two primary forms or directions compressive loading also increases expression of mechanical load applied to a tendon are tensile of MMP-13 and therefore breakdown of Type 1 loads, applied longitudinally along a tendon and collagen (Thornton et al 2010). compression, applied transversely across a tendon. Tensile loading or tension, occurs when Combinations of adverse loading scenarios the muscle contracts or is stretched along its are likely to be most problematic. In an animal length. Compression may occur intrinsically model, combinations of compression and high where fibre bundles within a tendon compress tensile loads were shown to be more damaging against each other or extrinsically where to tendons than either stimulus alone (Soslowsky tendons compress against structures such as et al 2002). other tendons or particularly where the tendon wraps around a bony prominence (Figure 5). Sedentary individuals may experience gradual changes in tendon tissue that has adapted to Compression results in adaptive changes to lower tensile loading (stress shielding) and/or increase tolerance of compressive loading – higher compressive loading. These changes large proteoglycans are produced and these bind make the tendon tissue relatively poorer at water and increase resistance to compression. absorbing tensile force and over time even Cartilage-like changes can also occur and the normal amounts of tensile loading may result tenocytes become more chondrocytic. Over in overload and further adverse responses within time, these areas can even ossify and present the tendon.

COMPRESSION

TENSION

Bone Tendon

Figure 5: Tensile and compressive loads along and across a tendon

Pre 1990 Tendinitis Paradigm

The era of ice and ultrasound

2002 Tendinosis Paradigm

Call to abdondon ‘the tendinitis myth’ 2012 Revisiting Inflammation

Inflammatory mediators recognised as major players 2017+

The search continues

For medications that block inflammatory mediators

PAGE 14 OF 36 Copyright Alison Grimaldi 2018 Historical Changes in Beliefs and Management Approaches

The role of inflammation in tendinopathy remains inflammation’ (Rees et al 2012). one of the most contentious issues in this field. Prior to 1990, the predominant paradigm was Major advances in immunohistochemistry and that tendon pathology was an inflammatory gene expression analysis have now been able tendinitis to be treated with anti-inflammatory to demonstrate in chronic painful tendinopathy, modalities (ice and ultrasound) and medications the presence of inflammatory cells such as (cortisone injection and oral non-steroidal anti- macrophages and mast cells and the pro- inflammatory drugs (NSAIDs)). While cortisone inflammatory cytokines derived from these cells. and NSAIDs had been shown to be useful in Inflammatory mediators such as substance reducing the pain associated with tendon P and prostaglandin E2 are also present in conditions in the short term, a lack of evidence higher concentrations in painful tendons, for their efficacy in the management of chronic released either from inflammatory cells or the tendinopathy suggested that there was more tenocytes themselves. Neurogenic inflammatory to this condition than a simple inflammatory processes also occur, whereby antidromic cascade. impulses (nerve impulses travelling in the opposite direction to normal) within nociceptive In 2002, Khan and colleagues implored health fibres deliver inflammatory mediators such as professionals to abandon the ‘tendinitis myth’ and Substance P directly into the local tissues. accept the irrefutable evidence that tendinopathy is a non-inflammatory pathology, based on The presence of leukocytes however is uncommon, histological evidence at the time, that classical indicating that this is a different process to the inflammatory cells were usually absent (Khan et more systemic, immune-driven inflammatory al 2002). For the next decade, inflammation was conditions like rheumatoid arthritis. In these barely mentioned with regard to tendinopathy, systemic conditions, medications developed treatments aimed instead at addressing either to inhibit cytokine pathways have been very a non-inflammatory ‘failed healing response’ useful but similar successes in interrupting the or reversing a degenerative continuum. In inflammatory processes involved in tendinopathy 2012, Rees et al. declared it was ‘time to revisit have so far been unsuccessful. The search for potential therapeutic medications that target inflammatory pathways in tendinopathy is a major focus of current scientific research in this field(Millar et al 2017). (See Millar et al 2017, (Rees et al 2012) and Scott et al 2015 for further information on inflammatory processes associated with tendinopathy)

A. COLLAGEN TEARING OR DISRUPTION MODEL

B. TENDON CELL RESPONSE OR CONTINUUM MODEL Stage 1: Reactive Tendinopathy Stage 2: Tendon Dysrepair Stage 3: Degenerative Tendinopathy

C. INFLAMMATORY MODEL

Copyright Alison Grimaldi 2018 PAGE 16 OF 36 While it is now clear that tendinopathy appears to be mediated through elements of an inflammatory response and that mechanical loading is a major player in tendon health and homeostasis, the actual trigger for the tendinopathic process remains disputed. Three main theories exist, the Collagen Disruption Model, the Tendon Cell Response Model and the Inflammatory Model which overlaps the other two.

A.Collagen Tearing or Disruption Model

The traditional collagen disruption model Almekinders and colleagues’ paper was one suggests that tendinopathy is a result of of the first to highlight flaws in the Collagen tensile overload, subsequent micro-rupture Disruption Model (Almekinders et al 2003). of collagen fibres in a healthy tendon and a Particularly for insertional tendinopathies, the classical inflammatory response. Chronic tendon regions that develop pathology are not tendinopathy is suggested to represent a ‘failed usually within the superficial side of the tendon healing response’ (D’Addona et al 2017). Cook and that carries most tensile load, but the deep, joint colleagues in their recent review of the models side of tendons which is relatively more stress suggest that ‘normal collagen fibres cannot shielded. Therefore, if tensile overload were the tear in vivo without substantial alterations in primary mechanism for pathology, we would the non-collagenous matrix’ (Cook et al 2016). It is expect to see pathology most commonly in not clear whether the cited articles establish this the superficial or high load (tensile) regions of as fact, however other key pathological features tendons. In addition, although tendinopathy is do not appear to be consistent with a theory of common is athletes, it is also very common in tensile collagen overload and breakage as the sedentary individuals with no history of tensile initiator of tendon disease. overload. Almekinders et al (2003) discussed the evidence around extra-cellular matrix changes in response to compression or stress shielding and suggested that weakening in tendon structure subsequent to these load scenarios may then predispose the tendon to collagen damage.

A new model was proposed by Cook and Purdam in 2009, that described a continuum of events driven by tenocyte response, resulting in changes in the extra-cellular matrix, initially reversible but becoming irreversible over time in the absence of load modification(Cook & Purdam 2009). The key premise of the model is that tenocytes initiate the whole cascade of biological changes that occur within a painful pathological tendon.

With reference to Figure 6 below, if we start with a normal healthy tendon and appropriately load that tendon, it will adapt positively with a net anabolic response, strengthen and then regain homeostasis. If the tendon is stress shielded or normal loading is significantly reduced, the tendon will weaken. If load is optimised early enough, this is reversible and the tendon can regain normal structure. If however a normal or stress shielded tendon is exposed to excessive load, and for the stress shielded tendon even moderate loads may eventually represent a situation of overload, the tendon may enter an early stage of tendinopathy. This is referred to as reactive tendinopathy. This phase has traditionally been called the proliferative stage and is reversible if loads are appropriately modified. If not, the pathological process progresses to tendon dysrepair and finally degenerative tendinopathy, at which point it is thought there is little chance of reversal.

The stages of tendinopathy described in this model attempt to delineate the chronology of intra- tendinous structural changes which may provide direction for the most appropriate management approaches at each stage.

Normal Tendon

Stress Shielded Normal Load Excess Load + other factors

Structural Change & Load Intolerance

Reactive Tendinopathy

optimised loadoptimised Tendon Dysrepair loadoptimised

Degenerative Tendinopathy

Figure 6: The Continuum or Tendon Cell Response Model (Cook & Purdam 2009)

PAGE 18 OF 36 Copyright Alison Grimaldi 2018 Stages of Tendinopathy Stage 1: Reactive Tendinopathy Stage 3: Degenerative Reactive tendinopathy was proposed as a Tendinopathy non-inflammatory tenocyte driven response usually following some form of overload (tensile or compressive, for example a burst In stage 3, there are areas of cell death related of unaccustomed activity or a direct blow to to apoptosis or pre-programmed cell death. the tendon). Tenocytes react by proliferating These areas may have little collagen, filled and producing large proteoglycans. These with products of matrix breakdown and small proteoglycans are produced more quickly blood vessels. Tenocytes may change shape, than small proteoglycans allowing a rapid cell- becoming rounder and more like chondrocytes mediated response to reduce tendon stress and – cartilage cells. Large areas of the matrix may increase stiffness. Large proteoglycans can be be disordered. It is common however to see produced from within minutes to a few days, heterogeneity of the matrix where there are whereas small proteoglycans can take twenty islands of degeneration amongst other stages days to produce. So the result is a large swollen of pathology and normal tendon. Degeneration is tendon due to the water binding properties of seen more commonly in older people, or younger the large proteoglycans. athletes with a chronically overloaded tendon. Degenerative stage tendons can rupture if exposed to high tensile load. Tendon rupture Stage 2: Tendon Dysrepair in a healthy tendon is extremely rare, so when rupture occurs there has been, in most cases an underlying degenerative process in place, In this stage, if loading has not been even if this has been asymptomatic. optimised, matrix breakdown continues. Characteristics of each stage are summarised Marked increases in large proteoglycans in Table 3. result in separation or cleavage of collagen fibres and matrix disorganisation. Changes are focal, rather than widespread and most common in the deeper, joint side of the tendon. There is suggested to be some reversibility of the pathology with general load modification and specific loading with targeted exercise.

1: Reactive Non-inflammatory Large proteoglycans Reversible with Tendinopathy cell response produced (aggrecan) optimised loading Proliferation Collagen remains organised Spindle shape Type I & II collagen

2. Tendon Marked increase in Some Dysrepair large proteoglycans reversibility Collagen fibres with optimised cleaved apart load & specific loading with Focal areas of matrix exercise disorganisation 3. Areas of Large areas of Little capacity Degenerative acellularity due disordered matrix for reversibility to apoptosis in areas of Tendinopathy Heterogeneity (pre-programmed degenerative cell death) More Type III collagen change Cells rounder Calcific deposits & more chondrocytic Increased vascularity

Table 3: Characterisics of the stages of tendinopathy proposed in the Continuum Model (Cook & Purdam 2009)

C. Inflammatory Model

The inflammatory model has overlap with each of the other models. In the recent revisiting of the continuum model by the original authors and some other colleagues (Cook et al 2016), it is restated, that although some inflammatory cells may be present, there does not seem to be a traditional inflammatory response. A traditional inflammatory response is one in which injured cells release histamine causing vasodilation and increases in vascular permeability to allow an influx of various cells (eg platelets, neutrophils, macrophages, fibroblasts) and extra fluid, resulting in physiological responses to the presence of these cells and the classic clinical signs of inflammation - heat, swelling, redness and pain (Scott et al 2004). Cook and colleagues (2016) do however state that ‘the inflammatory models and the continuum of pathology’ ‘may not be mutually exclusive. A tendon cell is mechanoresponsive, releasing cytokines in response to overload that then stimulate matrix remodeling (degradation and synthesis)’. While the catalyst remains in dispute, all models then agree that the presence of increased levels of inflammatory mediators underpins tendinopathic presentation – both at a microbiological and clinical level, cytokines closely linked with pain mechanisms.

PAGE 20 OF 36 Copyright Alison Grimaldi 2018 CHAPTER SIX THE PAIN OF TENDINOPATHY

WHAT IS THE SOURCE? The Role of Neuropeptides

THE VASCULAR CONNECTION

Copyright Alison Grimaldi 2018 PAGE 21 OF 36 What is the source? Where do these neurotransmitters The source of pain in tendinopathy is an ongoing focus of research, particularly with respect to come from? subsequent development of techniques to modulate pain mechanisms (See Rio et al 2014 for Catecholamines including epinephrine and review). Although neurovascular supply is usually norepinephrine (previously called adrenalin and rich in the tissues immediately adjacent to a nor-adrenalin) can be released as hormones tendon (tendon sheath, fat pad, bursae), it was from the adrenal medulla of the endocrine originally thought that tendons were aneural, but system and transmitted via the blood stream, sparse populations of small nociceptive C and but also as neurotransmitters in the sympathetic A delta fibres have been found within tendons. nervous system. Tenocytes themselves have These fibres have receptors for a number of also now been shown to both have receptors for neurotransmitters including catecholamines, catecholamines and to produce catecholamines acetylcholine, substance P and glutamate. themselves. Similarly, tenoctyes can bind and Neurotransmitters binding to these receptors produce acetylcholine and substance P and will cause the sensory fibres to fire off and carry can produce glutamate. A tenocyte expressing nociceptive information to the brain. Significantly these neuropeptides will have an effect on itself, higher levels of glutamate and Substance P are on its neighbouring cells and on C and A delta found within pathological tendons (Anderson et fibres. Tenocytes may not only be a key driver al 2008, Danielson et al 2009). for matrix change, but may be a key source of nociceptive and inflammatory mediators (Cook et al 2016, Rio et al 2014 ).

Substance P is commonly associated with pain and inflammation. Neurogenic inflammation is known to occur in persistent pain states, and may be a result of antidromic impulses travelling the reverse direction down the sensory nerves. This is the nervous system’s attempt at self-protection. By releasing substance P and CGRP, or calcitonin related gene peptide into the tissues, the purpose may be to create pain and therefore changes in behaviour and inflammation in an attempt to stimulate a healing process. (Figure 7)

PAGE 22 OF 36 Copyright Alison Grimaldi 2018 Sensory Sympathetic afferent efferent nerve NEUROPEPTIDES nerve fibre fibre C & A delta C Calcitonin Gene Related Peptide (CGRP) E Epinephrine & NorEpinephrine (Catecholamines) Acetycholine (Ach) E Ach

P Substance P

G Glutamate E Ach P G C Receptors P

Figure 7: Sources of and receptors for neuropeptides within a tendon

THE VASCULAR CONNECTION

Neovascularisation or ingrowth of new blood vessels, is commonly noted in degenerative stage tendinopathy and proposed to be linked with nociceptive processes (Alfredson & Ohberg 2005). With the new vessels comes new nerve supply and potentially greater nociceptive capability. Ablation of these vessels with sclerosing injections has however shown variable results with respect to reductions of pain and vascularity (Alfredson & Ohberg 2005, van Sterkenburg et al 2010). Furthermore, painful tendons don’t necessary have signs of neovascularisation and neovascularisation may be present in painfree tendons. Vascular ingrowth however may have close links with the biochemical processes involved in tendinopathy.

Copyright Alison Grimaldi 2018 PAGE 23 OF 36 Neuropeptides and pro- inflammatory cytokines are likely to play a significant role in the vascular changes associated with

tendinopathy. CGRP and acetylcholine both create vasodilation and increase vessel leakiness. Substance P has a potent angiogenic effect, that is, it stimulates new vessel formation. There has also been interest in a cytokine called VEGF – vascular endothelial growth factor. Remember, cytokines are messenger molecules released from cells. VEGF is produced by tenocytes. VEGF stimulates expression of MMP’s and inhibits expression of its inhibitor, TIMP. VEGF therefore encourages matrix destruction while also stimulating angiogenesis - the formation of new vessels. Like the neuropeptides, it also makes the vessels leaky. VEGF has been shown to be highly expressed in degenerative tendons but downregulated in normal tendons.

TNF alpha, another procatabolic or pro- inflammatory cytokine present at increased levels in pathological tendons, while known to stimulate matrix breakdown and tenocyte death, also upregulates expression of VEGF and CGRP. Via this mechanism, it is also implicated in the vascular effects associated with degenerative tendinopathy. TNF alpha and other cytokines are also produced by blood derived leucocytes. Increased blood supply provided by the neovessels may increase further the availability of TNF alpha and other cytokines.

This is one of the reasons why it has been suggested that systemic conditions with higher levels of circulating pro-inflammatory cytokines may play some role in tendinopathy. (Butler 2000, Pufe et al 2005, Schulze-Tanzil et al 2011, Scott et al 2008)

PAGE 24 OF 36 Copyright Alison Grimaldi 2018 CHAPTER SEVEN OTHER RISK FACTORS

Genetic Predisposition

Medications

Obesity & Metabolic Factors TENDINOPATHY Rheumatological Conditions

Age

Oestrogen & Menopause

Researchers have identified a number of Those with greater visceral fat have higher levels possible genes that may contribute to intrinsic of several pro-inflammatory cytokines (IL-6, predisposition to tendinopathy. In a more TNFa, CRP) which may then be negative for indirect manner, heritable genes for various tendon biological processes (Gaida et al 2008). tendencies towards adiposity, hyperlipaediemia It is possible to have high levels of visceral fat and anthropometric and other musculoskeletal with a larger waist and yet normal BMI, which characteristics may augment risk of developing may be why some studies show an association tendinopathy (Saunders et al 2016). between waist girth and tendinopathy but not BMI (Malliaras et al 2007).

Obesity and metabolic factors Large epidemiological studies in the general population have shown relationships between body mass index (or body weight or waist circumference) and the prevalence of tendinopathy (Scott et al 2015). It is unclear whether the mechanism is mechanical (higher body mass = higher loads on the tendon) or systemic (effect of circulating lipids). A study on the achilles tendon showed that heavier individuals had significantly greater tendon thickness, which could possibly reflect a positive Diabetes is another factor that may contribute adaptation to the higher loads. However, the to the links between obesity and tendinopathy. acute transverse strain response to exercise in Higher levels of blood glucose result in the heavier group was almost half that of lighter accelerated rates of glycation, the binding of individuals, suggesting that their thicker tendons glucose with lipids or proteins. Excess glycation were structurally deficient and unable to cope in turn results in higher levels of advanced with load in the same manner (Wearing et al 2013). glycation end products (AGE’s) which are known Increased levels of lipids in the blood to form cross-links within collagen fibres, thereby (hyperlipidaemia) may predispose to altering their structure and function. AGE’s also tendinopathy, particularly with inherited upregulate pro-inflammatory mediators and hyperlipidaemia (Scott et al 2015). apoptosis (tenocyte death) (Abate et al 2013).

PAGE 26 OF 36 Copyright Alison Grimaldi 2018 Age No high quality prospective randomised controlled trials are currently available to elucidate Older adults are at higher risk of tendon the effects of oestrogen supplementation (with pathology, the primary drivers appearing to or without exercise) on tendon health and be altered migration and reduced proliferation symptoms of tendinopathy in post-menopausal rate of tenocytes, resulting in ineffective repair women. One such study is currently underway processes and difficulties in maintaining a for women with gluteal tendinopathy (Ganderton healthy homeostatic state (Frizziero et al 2014). et al 2016).

Oestrogen & Menopause Tendinopathies such as gluteal tendinopathy are much more common in post-menopausal women (Segal et al 2007). Oestrogen deficiency has been shown to be linked with reductions in collagen tensile strength, decreases in collagen synthesis, fibre diameter and density and increased degradation of tendon structure. Furthermore, a lack of oestrogen may also result in changes in gene expression of other essential extra-cellular matrix molecules like proteoglycans, inflammatory mediators and growth factors. Associated decreases in TIMP’s (that control destructive MMP’s) have also been noted, predisposing to homeostatic imbalance and excessive destruction of the tendon matrix (Frizziero et al 2014).

The potential benefit of hormone replacement therapy is unclear. While oestrogen has such an important role in maintaining tendon health in females, oral administration may reduce circulating levels of pro-anabolic cytokines involved in collagen synthesis during physical activity (Frizziero et al 2014).

Copyright Alison Grimaldi 2018 PAGEPAGE 2727 OFOF36 36 Rheumatological induced mid-achilles tendinopathy and rupture is most common, but there have also been Conditions recent case reports for the gluteal and proximal hamstring tendons (Goyal et al 2016, Shimatsu et al 2014). It is important to be aware of the possibility that a painful tendinopathy, particularly an The risks are higher in those aged more than insertional tendinopathy may be subsequent to a 60 years, those with pre-existing tendinopathy rheumatological disorder such as gout, pseudo- and particularly those prescribed concomitant gout, spondyloarthropathies and rheumatoid glucocorticoid (steroid) therapy such as long arthritis (Jennings et al 2008). These conditions term oral steroids for systemic inflammatory may initially masquerade as sports injuries. conditions or even inhaled steroids for respiratory conditions (Kirchgesner et al 2014). A good subjective assessment can help indicate Questioning patients about medications is which patients may require blood testing or important and may help with early identification radiological investigation. Development of of flouroquinolone induced tendinopathy and symptoms without a history of injury or overload, avoidance of tendon rupture. The effects are prominent morning stiffness or night pain and usually resolved within 60 days of ceasing coexisting skin rashes, nail abnormalities, the medication but some take much longer bowel disturbance, iritis or conjunctivitis may to resolve (20 months) with residual damage raise suspicion of a systemic driver. A lack of in 10% of those effected (Kirchgesner et al 2014). response to a good load management and exercise approach or worsening of symptoms Even without the combination of fluoroquinolones, despite reductions in provocative loading may long term use of oral or inhaled glucocorticoids also indicate further investigation is warranted. for systemic conditions may contribute to the development of tendinopathy or tendon rupture Drug-Induced (Kirchgesner et al 2014). Tendinopathy Local injection of corticosteroids may also impact negatively on tendon structure and Some medications may also effect in rare circumstances result in rupture. Local tendon health. Fluoroquinolones, negative effects of corticosteroids include reduced tenocyte viability, proliferation and glucocorticoids and statins have collagen synthesis. Collagen disorganisation and been implicated in the development necrosis may result, particularly in association of tendinopathy and in some cases, with repeated injection, intra-tendinous injection long acting drugs and possibly when combined tendon rupture. with certain local anaesthetics (Dean et al 2014).

Fluoroquinolones, such as ciprofloxacin are broad Animal models have shown local anaesthetics spectrum antibiotics. Tendon toxicity and tendon such as ropivacaine 0.5% potentiate the toxic rupture are widely listed as potential side effects, effects on the tenocytes. Lidocaine may also although there remains uncertainty about the have a toxic effect on tendons, which is dose- exact mechanism. It has been shown that dependent. While the use of corticosteroid Ciprofloxacin enhances pro-catabolic cytokines, injection remains the first line medical treatment their stimulatory effect on MMP’s and therefore for many tendinopathies, ‘emerging clinical matrix destruction (Corps et al 2002). The effect evidence’ ‘shows significant long-term harms is usually of acute onset, occurring within the to tendon tissue and cells associated with first two weeks of treatment. Fluoroquinolone- glucocorticoid injections’ (Dean et al 2014).

PAGE 28 OF 36 Copyright Alison Grimaldi 2018 Statins, used in the treatment of hyperlipidemia and hypercholesterolemia, have also been reported to produce tendinopathy in a small percent of the population. Again, the mechanisms are not entirely clear, but thought to be related to an upset of the normal homeostatic balance between MMP’s and TIMP’s. There is significant disagreement in the literature regarding the influence of statins on tendon health. Two reviews report clear evidence of onset of tendinopathy or rupture, after months of statin therapy, resolution of symptoms once medication was ceased and return of symptoms on re-initiation of statin therapy (Dean et al 2014, Kirchgesner et al 2014). Another recent systematic review however concludes that the evidence for statin induced tendinopathy is weak and that Simvastatin in fact reduces the risk of tendinopathy (Teichtahl et al 2016). Prospective randomized controlled trials are required to clarify the impact of statins on tendons. These medications may affect an individual’s ability to respond to normal loading programs. Much further research is required, but care with loading in these populations and encouragement of weight loss where appropriate would represent due caution.

WHAT DOES IT ALL MEAN FOR THE CLINICIAN?

Understanding the mechanobiological processes involved in the development of tendinopathy underpins the generation of effective rehabilitation strategies. Contemporary practice should be guided by the evidence that has shifted us away from the traditional anti-inflammatory model and towards a model that considers the key role of tenocyte behaviour alongside the impact of inflammatory mediators from multiple sources.

The search continues for optimal mechanical and pharmacological methods of manipulating biological tendon processes to our advantage. In the meantime, our current understanding of the effect of patterns and types of loading and the influence of other risk factors allows development of robust and effective programs that reduce pain and improve load tolerance and function. The infographic that follows summarises how consideration of mechanobiological factors may influence your rehabilitation, maintenance and prevention programs (Figure 8). This does not undervalue the importance of addressing psychosocial factors which will influence an individual’s window for optimal loading, their response to a loading program and the ultimate success of a program with respect to pain and functional gains. Modern bio-psychosocial approaches should ensure that all aspects are addressed. The challenge for researchers and clinicians is to find the balance that will achieve the greatest gain for each individual.

PAGE 30 OF 36 Copyright Alison Grimaldi 2018 Catabolism > Anabolism Tendon weakens

PATTERN OF LOADING Rapid increase in load - training error or return to normal load after injury Inadequate recovery between loading sessions- 24-36hrs required TYPE OF LOADING Stress-shielding High compression, especially with added tension High tensile load, especially involving a stretch-shortening cycle

Catabolism = Anabolism Homeostasis

REGULAR OPTIMAL LOADING Window of optimal loading influenced by:

REHABILITATION REHABILITATION BIOMECHANICS Hormones AGE Rheumatological conditions NUTRITION Mental Health DIABETES PRIOR INJURY SEX ANATOMY IMMUNE FUNCTION Genes OBESITY SLEEP

Anabolism > Catabolism MAINTENANCE

OPTIMISE LOADING AND OTHER MODIFIABLE FACTORS MODIFIABLE AND OTHER LOADING OPTIMISE Tendon strengthens

PATTERN OF LOADING Graduated increases in loading Allow time for positive adaptation between loading sessions. Minimum 24-36hrs. Use load monitoring protocol. TYPE OF LOADING Slow heavy tensile loading Minimal compression - consider ranges ENCOURAGE REGULAR OPTIMAL LOADING & ATTENTION TO HEALTH FACTORS HEALTH TO & ATTENTION REGULARENCOURAGE OPTIMAL LOADING of motion that minimise compression & expose deep surface of tendon to tensile loading

Figure 8: The influence of mechanobiological mechanisms on rehabilitation strategies for painful tendinopathy

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Copyright Alison Grimaldi 2018 PAGE 35 OF 36 With over 25 years of clinical experience, Alison is Principal Physiotherapist at Physiotec Physiotherapy in Brisbane, Australia and an Adjunct Research Fellow in the School of Health & Rehabilitation Sciences, University of Queensland. Alison has a special interest in movement, muscle dysfunction and optimising musculoskeletal loads and is a committed lifelong learner.

Alison completed a Bachelor of Physiotherapy at the University of Queensland in 1990, a Masters of Sports Physiotherapy in 1997, and her Doctorate in Philosophy in the Field of Physiotherapy (PhD) in 2008. Her PhD studies were concerned with improving our understanding of hip muscle function and the relationship with hip joint pathology and weightbearing stimulus. Alison continues to be passionate about extending our understanding of why we develop problems around the hip and pelvis, and what we can do to most effectively prevent and manage these problems. She has ongoing involvement in research studies investigating lateral hip pain, proximal hamstring tendinopathy, groin pain and function of the deep hip flexors and rotators.

It is one of Alison’s core beliefs that research should be relevant to clinical practice and helping the patients we treat every day, and that physiotherapists in the community should have access to this valuable information to allow them to transfer this knowledge into clinical practice as quickly as possible. To this end, Alison continues to publish, present and provide practical workshops for other health professionals. Alison has published many peer-reviewed papers in scientific journals, has contributed detailed information freely accessible via podcasts by PhysioEdge (itunes) and the British Journal of Sports Medicine (SoundCloud), and has recently contributed to 3 leading physiotherapy and sports medicine text books. She has presented her research and clinical teachings in Australia, New Zealand, England, Ireland, Scotland, Wales, Singapore, HongKong, the Netherlands, France, Belgium, the Unites States of America, Canada and the United Arab Emirates.

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