invents the steam engine. Outside, the streets are full of horseâdrawn carriages. The mail coach from Birmingham arrives, swaying through the street with a.
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59.0 56.5 54.0 51.5 49.0 46.5 44.0 41.5 39.0
Fig. 6 View of the proximal articular surface of the proximal phalanx. Proteoglycan content (in μg/mg dry weight) over the surface is made visible using cartographic techniques. The local differences ( “topographical heterogeneity”) can be seen easily.
pressure (MPa) 43.74 38.81
dors.
39.95 29.05 24.15
med.
lat.
19.26 14.36 9.47 4.57
palm. non-contact area
Fig. 7 View of the proximal articular surface of the proximal phalanx. The colours represent the pressure (in MPa) the joint is subjected to when the horse is galloping. Pressure is highest at the dorsal rim and less in the central area of the joint. When the horse is standing or walking, the dorsal rim is not loaded at all (noncontact area), but the central part is. Med: medial (inside of limb); lat: lateral (outside of limb); dors: dorsal (front side of limb); palm: palmar (backside of limb).
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Man and Horse: Brothers in Arms Inaugural Lecture delivered with respect to acceptance of the office of Professor of Equine Musculoskeletal Biology at the Faculty of Veterinary Medicine, Utrecht University on Monday 14th April 2008 by Dr. P. René van Weeren
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Right Honourable Rector Magnificus, Professorial colleagues, lecturers and employees of the University, Lady and gentlemen students, Family, friends and colleagues from outside the University.
Esteemed listeners, Ladies and Gentlemen,
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It is a long‐standing academic tradition to accept the appointment to a chair by giving an inaugural lecture. The name of the chair to which I was appointed nearly a year ago is Equine Musculoskeletal Biology. In the next 30 minutes I would like to say a few words on all 3 components of this name: equine, musculoskeletal and biology, in the hope of clarifying both what is meant by these terms, and the relationships between them. We shall start, as we ought to, at the beginning. In fact, we go back 25,000 years and arrive in the slightly warmer period between the last two ice ages. In a small valley on the windswept and ice‐ cold tundra of what we nowadays call Ukraine we see a lonely little girl taking care of a new‐born foal that belonged to the Przewalski mare she has just killed for food. Some years later she will astound her compatriots when she gallops past, sitting on the now fully grown animal, her golden hair waving in the wind. Many of you will recognise in this short story Ayla and her horse Whinney, characters from the novel series “the Earth’s Children”, by the American novelist Jean Auel, a well‐documented but heavily romanticised epic story about our direct forbearers, who we nowadays refer to as the Cro‐Magnon peoplei. In fact, Ayla made her appearance 20,000 years too early because, although there may have been incidental earlier cases, the horse was not domesticated until 5,000 years ago, as one of the last major species to have been domesticatedii. Nevertheless, the story of Ayla and Whinney perfectly reflects the fascination of mankind for the speed and grace of the horse and the resulting emotional bond between man and horse, which is stronger than with any other species, except the dog. The domestication of the horse compels us to consider “equine’ and “musculoskeletal” as being intricately linked, even inseparable, items because the horse is one of very few species that were domesticated because of their locomotive capacities, i.e. their musculoskeletal system. After its domestication, the horse evolved as one of the pillars of human society in many parts of the world, at first for warfare, where the horse was the most important innovation before the invention of gunpowder, but later also for more peaceful purposes in agriculture and transport. During the millennia that the horse was so pivotal to society, the species also appealed aesthetically to man. There is no animal that has been depicted more often in works of art, and there are many mythical horses and horse‐like beings, including the Centaur: half man, half horse. 5
When we make the next stop in our journey through time, the horse is still unrivalled as the motor of society. Close your eyes, let the walls surrounding you fade and imagine yourself in the magnificent lecture hall of the venerable Royal Society of London. It is June 2nd, 1743. James Watt is already amongst us, but just 7 years old; 26 more years will pass before he invents the steam engine. Outside, the streets are full of horse‐drawn carriages. The mail coach from Birmingham arrives, swaying through the street with a blind‐drunk driver, who is being cursed by the captain of a contingent of Royal Guards on their way to Buckingham Palace. Inside, the ambience is solemn and the learned audience listens attentively to a lecture given by the medical doctor and scientist William Hunter (Fig. 1), who has performed a very detailed study on the structure, function and diseases of articular cartilage. In this discourse, in which he displays a surprising knowledge of the Fig. 1 essential characteristics of articular cartilage, William Hunter (1718- 1785) he states the following: “If we consult the standard chirurgical writers from Hippocrates down to the present age, we shall find, that an ulcerated cartilage is universally allowed to be a very troublesome disease; that it admits of a cure with more difficulty than a carious bone; and that, when destroyed, it is never recoverediii. “ This citation leads me to a first short digression. I have always been very interested in the use of languages and this quote of Hunter shows nicely how beneficial the absence of an institution as the Dutch‐Flemish Language union (“Taal Unie”) has been for the English language: even after more than 250 years this text can be read and understood easily, even by a non‐native speaker. Use of language is a hot topic at this moment at the Utrecht Veterinary Faculty. It appears that a dreadful blunder is about to be made, since there are rumours that Dutch will be ratified as the working language of the Masters programme that is currently being designed. Such a choice is not only in contradiction with the Faculty’s own Strategy Report, but could 6
be classified as an almost reactionary action since it flies in the face of current trends of internationalisation and globalisation. It is not yet too late, and I sincerely hope that future generations of vets will have no reason to accuse the current managers of the Faculty for a flagrant lack of vision. But this, as I said, is an aside. The quote from Hunter is known to all cartilage researchers throughout the world and concisely presents the essence of the problem of osteoarthritis (OA), in lay terms “joint wear”. Osteoarthritis is a very big problem in man. In 1997, the costs of OA and other joint ailments in the US alone were estimated at $ 187 billion of direct costs and another $ 86 billion of indirect costsiv. Although not life threatening, joint diseases substantially diminish the quality of life for hundreds of millions of people. Unfortunately, Hunter’s statement is still valid today since OA is still an incurable disease. Many people with end‐stage OA will end up with artificial joints, with all the complications and costs that this entails. Have we then not made any progress since Hunter’s days? Of course we have; nowadays we know much more about articular cartilage and how it reacts to the environment. Here we arrive at the 3rd item of our title: biology. Biology is a contraction of two Greek words: βίος (life) and λόγος (word, but also reason). Biology is the central science of the entire living world. The biology of articular cartilage is fascinating. This is mainly because it is tissue that has to cope with very contradictory demands. On the one hand it has to withstand the forces generated by locomotion, as does the skeleton. These forces are considerable. A galloping horse can reach speeds of 40 mph, which provokes forces of several tonnes in certain joints. Therefore, the tissue must be very strong. On the other hand, it can not be as rigid as bone because it also has to function as a shock absorber to prevent joint damage. Finally, it has to have a smooth surface to allow supple, almost Fig. 2 Schematic drawing of articular frictionless motion of the joint. Nature has cartilage 7
solved this problem in a very ingenious way. Articular cartilage is made up of about 95% extracellular matrix and not more than 5% cells. There are no mechanically disturbing elements such as blood Fig. 3 Two-dimensional representation of Benninghoff’s arcades vessels or nerves, a considerable exception within the mammalian body (fig. 2). It is the extracellular matrix that determines the biomechanical characteristics of the tissue. The 3 principal components of this matrix are collagen fibrils, proteoglycan aggregates and water. The collagen fibrils are arranged in an arcade‐like structure that was described as early as 1925 by Benninghoffv (fig. 3). Collagen is a very strong protein and also the most abundant protein in the body, albeit mostly in a slightly different form. Interspersed within the network of collagen fibrils are the proteoglycan aggregates: a combination of proteins and sugars, which attract water as a result of their negative charge (fig. 4). Therefore, articular cartilage can be seen as a strong network which has an intrinsic tension because of the swelling pressure of the hydrophilic proteoglycan aggregates. If pressure is exerted on this system by loading the joint, the mechanical forces will overcome the electrohydrostatic forces and water will be squeezed out; the cartilage gives and is thus elastic. When the joint is unloaded, the Fig. 4 Schematic drawing of the extracellular reverse occurs. With this matrix of articular cartilage. Shown are the repeated in and outflow of fluids, collagen fibrils with in between the nutrition and waste products proteoglycan aggregates, which are connected to the collagen fibrils via hyaluronic acid (HA). will enter or leave the tissue, The proteoglycan aggregates are made up of a respectively (fig. 5). This core protein with perpendicular to it negatively mechanism compensates for the charged sugar moieties. 8
absence of the blood vessels that fulfil this role almost everywhere else in the body. The composition of the extracellular matrix is thus such that the tissue can handle the forces generated by locomotion. The nice thing is that this is a very finely regulated system, since there is an exact match between the varying loads applied over the surface of a given joint and the biochemical composition of the affected sites on that surface. Pieter Brama showed this so‐called ‘topographical heterogeneity’ of the cartilage matrix very elegantly in the metacarpophalangeal joint of the horse when he took cartilage samples at many sites and finely mapped the differences in composition using cartographic techniquesvi (fig. 6, see inside cover). He did the same with the varying loads within the joint and was able to show that sites that are constantly loaded when the horse is weight‐bearing are characterised by a relatively high content of proteoglycans, whereas sites that are only intermittently, but more heavily, loaded have a higher collagen contentvii (fig 7, see inside cover).
Fig. 5 Schematic drawing of the biomechanical principle of articular cartilage. A: unloaded (c=collagen fibrils, p=proteoglycan aggregates); B: when loaded, tissue fluid is squeezed out, taking waste products with it; C: a new equilibrium has formed, the cartilage has yielded somewhat (i.e. is elastic). If unloaded, a reverse process will take place.
This topographical heterogeneity is nice, but the fast thinkers amongst you will immediately ask: but what is the situation in the newborn foal? In utero the foal may make some swimming movements, but the joints are never really loaded. This is true, and it means that there are two possibilities: either the topographical heterogeneity is genetically determined, or it develops during early life. The latter turns out to be the case. A foal is born with what we call a “blank joint” and the topographical heterogeneity in the horse is formed during the first year, indeed for the larger part during the first 5‐6 months, of life. This process is called “functional adaptation” and is 9
directed by biomechanical loadingviii. Development is therefore directly linked to the amount of exercise an animal is subjected to during the first months of life. In osteology, the science of bones, Wolff’s law has been widely accepted since the end of the 19th centuryix; it states that bone will adapt in density and in the direction of its trabecular structures to loading. In fact, a similar principle exists for the collagen network of articular cartilage. There is, however, one very essential difference with bone. Bone turnover remains high throughout life. Therefore, the adaptation to load will continue to occur until a very advanced age. Turnover of the collagen component of articular cartilage is also very high in young, growing individuals, but extremely low in mature animals (or people). In man the turnover time of mature articular collagen has been estimated at 350 yearsx. This means that the process of functional adaptation as it occurs in the collagen network of the young individual is a very crucial process that determines “cartilage quality” for life. It also underlines the enormous importance of sufficient exercise at a young age. In this respect, it is interesting to see how nature works. It has been shown that the spontaneous activity of foals kept at pasture for 24h per day, is virtually identical to the exercise undertaken by feral foals xi. This seems, therefore, to be a self‐regulating mechanism. It should be realised, however, that things change dramaticlly when we decide that we want to produce our foals as early as possible in the season, since the consequence is usually that they cannot go outside, for climatic reasons. In this light, early season breeding might be seen as horse‐unfriendly and a interesting point for the discussion on equine welfare that has recently arisen. It is also possible to influence the make‐up of the extracellular matrix of cartilage in the other direction. Some time ago we took part in a large project together with our partners in the Global Equine Research Alliance (Massey University, New Zealand; Royal Veterinary College, UK and Colorado State University, USA) in which young foals received additional training on top of continuous access to pasturexii. It appeared that this early extra exercise accelerated the normal maturation process, and the formation of topographical heterogeneityxiii. Therefore, the possibility exists that we might be able to better arm our horses for later athletic demand by exposing them to well‐designed exercise regimens as foals. This research in foals has drawn much attention from the human field, where there is genuine concern about the potential consequences of the current sedentary lifestyle of many children with 10
regard to the susceptibility to OA in 30 or 40 years time xiv. When I see my young children run through the house from A to B in the most inefficient way possible, I always have to think that they may, unknowingly, be making a very wise decision. Overall, articular cartilage therefore follows a neat and well thought‐out concept that is very functional. But what happens when it goes wrong? When there is damage to the collagen network? That will, of course, lead to disaster because in that event the proteoglycan aggregates will fall out and the whole system will ‘crash’. This is indeed the case in osteoarthritis. And here the bottleneck is the gigantic turnover time of a couple of centuries for mature collagen. This means that everyone in this room of, say, 16 years and over (i.e. the vast majority), who have some kind of cartilage damage (again the majority I’m afraid), will have their damage repaired in approximately 350 years. This is a very reassuring long‐term prospect for your cartilage, but the problem is that the rest of you won’t be there to celebrate the recovery. This in a nutshell is the biological background of Hunter’s statement and the reason why OA is still such an invalidating disease. It is also the reason why joint disorders in general, and osteoarthritis more specifically, is one of the most important focus areas of a rapidly rising new discipline in medicine that is called regenerative medicine: medical interventions that aim to restore the function of certain tissues. With the term “regenerative medicine” a new link between man and horse emerges. The principles of articular cartilage biology are not essentially different between man and horse (or other mammals). This makes the horse an excellent model for human orthopaedics because of its size, the heavy biomechanical loading of its joints and the existing expertise with respect to biomechanics and gait analysis for this species. There is increasing recognition of the suitability of the horse as an experimental animal and at present the American Food and Drug Administration (FDA) will not allow the introduction of certain orthopaedic procedures or devices to the human market unless experiments on horses have been performed. Our research group sees this as an important niche and we have, for example, already done some preliminary research into the effects of the implantation of collagen scaffolds seeded with stem cells into artificially created defects in equine cartilage. It is the intention to expand this type of 11
work, which fits excellently into the Faculty‐wide Tissue Repair programme, substantially in the coming years. We recently started a close and much appreciated collaboration with the Orthopaedic Research Group of the Utrecht Academic Medical Centre. The important translational value of orthopaedic research in the equine species does not mean that we intend to forget the horse itself. It is very important, from both a veterinary and an ethical viewpoint, that the horse, virtually alone among the animal species, is not only an experimental animal and a model for man, but also an important target animal in its own right because of the importance of the musculoskeletal system and disorders thereof for this species. Apart from helping mankind, the horse itself will also therefore benefit directly from this type of research. The “horse as model” is the starting point for a second short digression on that other important academic task: teaching. In veterinary medicine the horse has always been used as a model animal, based largely on the importance of the species for society. That importance declined rapidly because of mechanisation after World War II. Just as in law, however, changes in education tend to lag behind societal development. As a result, the horse has gradually lost its role as a primary model in teaching and is now used rather minimally in the present‐day bachelor curriculum. However, recently the horse has not only become more important in a scientific sense, but has also made a glorious comeback in society as a sports and leisure animal. Equestrian sports place second after football in the Netherlands and the annual turnover of the equine sector is at € 2 billion about twice that of our world famous flower‐bulb industry. Municipal and provincial country planners have already expressed their concern about the “horsification” of the countryside. Therefore, I predict that in, say, 12 years, and with the current rate of curriculum renewal that will be the second curriculum after the original bachelor‐masters revolution, the horse will have regained its prominent position in teaching. At least in what can be called the medical‐veterinary part of the curriculum that focuses at individually housed animals; for the food species, we will probably have to ask the agro‐veterinary cartel in Wageningen. But, let’s get back to the core business. We were talking about the horse as both a model and as a target animal for scientific research into the 12
musculoskeletal system. Besides articular cartilage, tendons are excellent subjects for this so‐called translational research. The horse is a very efficient runner and uses its flexor tendons to temporarily store energy as elastic energy when the foot touches down. That energy returns as kinetic energy at take‐ off for the next stride. The muscles serve to support this spring‐like function of the tendonsxv (fig. 8). These flexor Fig. 8 Schematic drawing of the structure tendons are referred to as energy of a tendon, from (macroscopically visible) fasciculi to the underlying storing tendons. The human molecular structures. Achilles tendon functions in much the same way and is even anatomically very similar to the equine superficial digital flexor tendon. Given this similarity and the fact that tendon research in the horse is, perhaps surprisingly, ahead of tendon research in man, there is an excellent base for collaboration with the human field. For this reason I am very pleased with the recently initiated collaboration in the field of clinical tendinopathy with the Erasmus Medical Centre in Rotterdam. We even have a proper liaison officer in the form of Hans van Schie, who has a part‐time appointment in both research groups and who himself has performed cutting‐edge research on the quantification of ultrasonographic changes in the tendons of man and horse xvi. Our current research focuses on the evaluation of new therapies and the development of good models, and we hope that we can contribute with this research to a substantial improvement in the treatment of tendon lesions. That is important for man, but may be even more important still for the horse where tendon disorders rank either first or second in causes of wastage, depending on the equestrian discipline. This also makes this type of research, like that on cartilage disorders addressed earlier, a good investment target for the equine industry. Not only because of expected improvements in the therapy or prevention of lesions leading to better performance, but also to make clear to the public that the equine sector takes the issue of equine welfare seriously. The term “welfare” justifies another short digression because this is an item that is in the heart of every vet. Animal welfare is an important political 13
item these days. We have a Pro‐animal Party in Parliament and increasingly strict legislation on animal experimentation. That is as it should be, but there is still some imbalance. Some time ago Piet Borst, the former director of the Dutch Cancer Institute, wrote a column about how we treat mice, observing that there was a huge discrepancy in status between two populations of mice in the building where he works. On the one hand were the experimental mice, where everything done to or with them is strictly regulated and has to be extensively justified; on the other hand were the wild mice in an empty part of the building that was to be renovated, which were en masse exterminated using a nasty poison. This selective attention for animal welfare is not uncommon. There is always a commotion, and sometimes with good reason, about abuses in the so‐called bio‐industry. However, nobody ever says anything about that elderly couple, both of them paying members of the Association against Vivisection, who prolong the life of their 10‐year‐old boxer, suffering from a metastasised osteosarcoma, by a few months by giving radiation or chemo‐therapy because they cannot bear to miss their companion. That is also a form of animal abuse. In both cases, the own interests of people, be it financial or emotional, prevail over the interests and the welfare of the animal. In fact, almost everything we do with animals is driven by our own self‐interest, whether we buy thousands of sheep in Poland and transport them to Spain to sell them at a profit, sit on a horse’s back to win competitions, or keep a dog because we are otherwise lonely. We’ll have to be courageous enough first to admit this, then to accept it and lastly to conclude that it is our task to find a balance between that self interest and respect for the individual animal. With this digression we have already entered an area of a somewhat more esoteric character than the biology of the musculoskeletal system. This is a good moment to proceed to the last, more general part of this lecture. The chair I have been appointed to is principally a research chair and then the question arises: what is science and why do we do research? There is general consensus that modern science has its roots in the cultures of Ancient Greece and Asia Minor dating from about 800 BC. The schools of thinking that originated in those days later produced famous philosophers such as Socrates, Plato and Aristotle. In those days science had three components: making observations, thinking about those observations and 14
lastly the formulation of hypotheses and models based on the two first parts of the process. Experimental testing did not become part of science until the 17th and 18th centuries AD. There is now little doubt that experimental testing is an essential and necessary step in science and one that cannot be missed. However, at present there seems to be a tendency to overemphasise this part of science at the cost of the other components. Most students who do an experiment eagerly check whether there are statistically significant differences in the results and if so happily lean back thinking that the experiment is over and was a success. Of course this is not always true. Significant results are a prerequisite, but there is more than that. Are the results also biologically relevant? Do they fit in with existing theory, or do we have to adapt that theory? This requires real academic thinking, which is not the same as calculating p‐values and making error analyses, however valuable these analytical tools may be. Cogito ergo sum (I think, therefore I am) is a famous saying of the French philosopher René Descartes, who is well known in Utrecht because he lived here for a whilexvii. Computo ergo sum (I calculate therefore I am) is a fantastic motto for a chain of supermarkets, but has nothing to do with science. Why do we do research? If I adhere to the recent Faculty guidelines, the answer is simple: to publish as much as possible in the highest‐ranking journals in my scientific field and to show that I have great earning capacity by generating large flows of additional research money, preferably from prestigious sources. Of course I am well aware of how things work in practice and I wholeheartedly support the idea that research output should be measurable. I also think that the Institute of Veterinary Sciences of Utrecht’s Veterinary Faculty has developed some excellent tools for measuring scientific productivity, much better than those used in many other research environments. Nevertheless, I think that it is good to realise from time to time, and today may be a good opportunity for this, that the real goal of science is of course not that paper in Nature or Science and not the acquisition of that prestigious project. If that were the case, the academic world could rightfully be accused of irresponsible narcissism. It is the task of the academic world to serve Society at large, which in this case can be defined as the entire planetary ecosystem. At present, mankind is in a critical transitional period because of the disappearance of many technical limitations (which is, by the way, due to scientific progress), this compels a change from a situation where choices were largely dictated by 15
environmental conditions to a situation where conscious choices not only can, but have to be made. Based on our supposed cerebral superiority we long ago proclaimed our own species as the most important, but a simple look in today’s newspapers shows that we have great difficulty in living up to our leadership role. Science can and should help. Therefore, science is absolutely not non‐normative, to recall an old discussion from the sixties. The life sciences in particular can be of great help because of the knowledge and insight they generate about nature. We can never go back to the intuitive solidarity with nature of the days of Ayla and her horse Whinney; we’re too numerous for that and society is too technology‐driven. However, as the species Homo sapiens, we are an integral part of nature, whether we like it or not, and it is good to realise this. Some of the North American Indians talked about “brother horse” when they talked about their horses and I hope to have made clear to you that there is more in common between man and horse (and other mammalian species) than most probably think. Science can provide insight in important biological concepts, but probably as important is the academic reflection as it was practised, not swayed by the issues of the day, by our godfathers from Greece and Asia Minor. Knowledge and wisdom are both crucial if we want to take the most appropriate decisions for the future of the ecosystem we dominate. To end I would like to say a few personal words of thanks. It is gratifying to stand here and to deliver this speech, but this would not have been possible without the help, direct or indirect, of many people, or without their inspiration. First of all I would like to thank my parents, who fortunately were able to be here despite recent serious health problems. I am also glad that my brother could be here together with his family and that my eldest daughter, who is about to embark on her own academic career this year, is in the audience. The youngest two are –hopefully‐ happily playing in a room elsewhere in this building. I want to give sincere thanks to my parents‐in‐ law, who are always a great help and who are the best child minders I ever met. In the professional sphere it is impossible to mention everybody. I will therefore only make the exception for people who made it possible for me to pursue an academic research career. These are Professor Kersjes, who offered me the opportunity to embark on a PhD programme shortly after becoming a staff member at the former Department of General and Large 16
Animal Surgery; this was the basis of everything. And professor Barneveld, who has greatly facilitated the academic career that has culminated in my current position. Further, I would like to thank my colleagues from the current Department of Equine Sciences and the former Department of General and Large Animal Surgery for their collegiality and the always far from boring working environment. There are two places of honour left in these acknowledgements. One of these is of course for my wife, Madelon, who has always been very supportive and above all is a source of great inspiration. The other is for the many horses I have encountered during my career, many of them as patients, some as experimental animals. The silent trust they seem to have has always been a great inspiration and reminds me of what it is all ultimately about in veterinary medicine: hominum animaliumque saluti, or: for the well being of man and animals. I have spoken.
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Auel, J.M. (1987) The Valley of Horses. London : Stodder & Houghton Ltd. Dunlop, R.H. and Williams, D.J. (eds.) (1996) Veterinary Medicine. An illustrated History. St. Louis : Mosby. iii Hunter, W. (1743) On the structure and diseases of articulating cartilage. Philos. Trans. R. Soc. Lond. 42, 514521. iv Yelin, E., Cisternas, M.G., Pasta, D.J., Trupin, L., Murphy, L. and Helmick, C.G. (2004) Medical care expenditures and earnings losses of persons with arthritis and other rheumatic conditions in the United States in 1997 : total and incremental estimates. Arthritis Rheum. 50, 2317-1326. v Benninghoff, A. (1925) Form und Bau der Gelenkknorpel in ihren Beziehungen zur Function. II. Der Aufbau des Gelenkknorpels in seinen Beziehungen zur Function. Z. Zellforsch. Mikrosk, Anat. 2, 783-862. vi Brama, P.A.J., TeKoppele, J.M., Bank, R.A., Karssenberg, D., Barneveld, A. and van Weeren, P.R. (2000) Topographical mapping of biochemical properties of articular cartilage in the equine fetlock joint. Equine vet. J., 32(1), 19-26. vii Brama, P.A.J., Karssenberg, D., Barneveld, A., van Weeren, P.R. (2001) Contact areas and pressure distribution on the proximal articular surface of the proximal phalanx under sagittal plane loading. Equine vet. J., 33, 26-32. viii Brama, P.A.J., TeKoppele, J.M., Bank, R.A., Barneveld, A., van Weeren, P.R. (2002) Development of biochemical heterogeneity of articular cartilage: influences of age and exercise. Equine Vet. J. 34, 265-269. ix Wolff, J. (1892) Das Gestez der Transformation der Knochen. Berlin : August Hirschwald. x Maroudas, A. (1980) Metabolism of cartilaginous tissues : A quantitative approach. In : Studies in Joint Disease. Vol. 1., eds : A. Maroudas and J. Holborrow. Tunbridge Wells : Pitman Medical. xi Kurvers, C.M.H.C., van Weeren, P.R., Rogers, C.W. and van Dierendonck, M.C. (2006) Quantification of spontaneous locomotion activity in Warmblood foals kept in pastures under various management conditions. Am. J. Vet. Res. 67, 1212-1217. xii Rogers, C.W., Firth, E.C., McIlwraith, C.W., Barneveld, A., Goodship, A.E., Kawcak, C.E., Smith, R.K.W. and van Weeren, P.R. (2008) Evaluation of a new strategy to modulate skeletal development in Thoroughbred performance horses by imposing track-based exercise during growth. Equine vet. J. 40, 111-118. xiii Van Weeren, P.R., Firth, E.C., Brommer, H., Hyttinen, M.M., Helminen, H.J., Rogers, C.W., DeGroot, J. and Brama, P.A.J. (2008) Early exercise advances the maturation of glycosaminoglycans and collagen in the extracellular matrix of articular cartilage in the horse. Equine vet. J. 40, 128-135. xiv Helminen, H.J., Hyttinen, M.M., Lammi, M.J., Arokoski, J.P., Lapvetelainen, T., Jurvelin, J., Kiviranta, I. and Tammi, M.I. (2000) Regular joint loading in youth assists in the establishing and strengthening of the collagen network of articular cartilage and contributes to the prevention of osteoarthrosis later in life : a hypothesis. J. Bone Miner. Metab. 18, 245-257. xv Wilson, A.M., McGuigan, M.P., Su, A. and van den Bogert, A.J. (2001) Horses damp the spring in their step. Nature 414, 895-899. xvi Van Schie, J.Th.M. (2004) Ultrasonographic tissue characterization of equine superficial digital flexor tendons. Development and application of computer-aided image analysis. Thesis, Utrecht University. xvii Descartes, R. (1644) Principia philosophiae. Amstelodami : Ludovicum Elzevirum. i
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