Mechanisms of synovial joint and articular cartilage formation: recent advances, but many lingering mysteries

Synovial joints are elegant, critically important, and deceptively simple biomechanical structures. They are comprised of articular cartilage that covers each end of the opposing skeletal elements, synovial fluid that lubricates and nourishes the tissues, ligaments that hold the skeletal elements in check, and a fibrous capsule that insulates the joints from surrounding tissues. Joints also exhibit an exquisite arrays of shapes and sizes, best exemplified by the nearly spherical convex femoral head articulating into a nearly spherical concave hip acetabulum, or a phalangeal joint with two condyles on the distal side articulating in reciprocally-shaped sockets on the opposing proximal side. Though few in number, joint tissues are highly specialized in structure and function. This is illustrated by articular cartilage with its unique extracellular matrix, unique biomechanical resilience, its largely avascular nature, and its ability to persist through life with minimal turnover of its cells and components. The fact that interest in synovial joints has remained unabated for decades is a reflection of their fundamental importance for organism function and quality of life, and for their susceptibility to a variety of acquired and congenital conditions, most importantly arthritis. This has led to many advances in this field that encompass molecular genetics to biomechanics to medicine. Regrettably, what continues to be poorly understood are the mechanisms by which synovial joints actually form in the developing embryo. If available, this information would be not only of indisputable biological interest, but would also have significant biomedical ramifications, particularly in terms of designing novel tissue regeneration or reconstruction therapies. This review focuses on recent advances in understanding the mechanisms of synovial joint formation in the limbs, and places and discusses the information within the context of classic studies and the many mysteries and questions that remain unanswered.     

Joint morphology in the insect leg: evolutionary history inferred from Notch loss-of-function phenotypes in Drosophila

Joints permit efficient locomotion, especially among animals with a rigid skeleton. Joint morphologies vary in the body of individual animals, and the shapes of homologous joints often differ across species. The diverse locomotive behaviors of animals are based, in part, on the developmental and evolutionary history of joint morphogenesis. We showed previously that strictly coordinated cell-differentiation and cell-movement events within the epidermis sculpt the interlocking ball-and-socket joints in the adult Drosophila tarsus (distal leg). Here, we show that the tarsal joints of various insect species can be classified into three types: ball-and-socket, side-by-side and uniform. The last two probably result from joint formation without the cell-differentiation step, the cell-movement step, or both. Similar morphological variations were observed in Drosophila legs when Notch function was temporarily blocked during joint formation, implying that the independent acquisition of cell differentiation and cell movement underlay the elaboration of tarsal joint morphologies during insect evolution. These results provide a framework for understanding how the seemingly complex morphology of the interlocking joint could have developed during evolution by the addition of simple developmental modules: cell differentiation and cell movement.     

Joint development in the Drosophila leg: cell movements and cell populations

Flexible joints separate the rigid sections of the insect leg, allowing them to move. In Drosophila, the initial patterning of these joints is apparent in the larval imaginal discs from which the adult legs will develop. Here, we describe the later patterning and morphogenesis of the joints, which occurs after pupariation (AP). In the tibial/tarsal joint, the apodeme insertion site provides a fixed marker for the boundary between proximal and distal joint territories (the P/D boundary). Cells on either side of this boundary behave differently during morphogenesis. Morphogenesis begins with the apical constriction of distal joint cells, about 24 h AP. Distal cells then become columnar, causing distal tissue nearest the P/D boundary to fold into the leg. In the last stage of joint morphogenesis, the proximal joint cells closest to the P/D boundary align and elongate to form a "palisade" (a row of columnar cells) over the distal joint cells. The proximal and distal joint territories are characterised by the differential organisation of cytoskeletal and extracellular matrix proteins, and by the differential expression of enhancer trap lines and other gene markers. These markers also define a number of more localised territories within the pupal joint.     

Mechanical influences on morphogenesis of the knee joint revealed through morphological, molecular and computational analysis of immobilised embryos

Very little is known about the regulation of morphogenesis in synovial joints. Mechanical forces generated from muscle contractions are required for normal development of several aspects of normal skeletogenesis. Here we show that biophysical stimuli generated by muscle contractions impact multiple events during chick knee joint morphogenesis influencing differential growth of the skeletal rudiment epiphyses and patterning of the emerging tissues in the joint interzone. Immobilisation of chick embryos was achieved through treatment with the neuromuscular blocking agent Decamethonium Bromide. The effects on development of the knee joint were examined using a combination of computational modelling to predict alterations in biophysical stimuli, detailed morphometric analysis of 3D digital representations, cell proliferation assays and in situ hybridisation to examine the expression of a selected panel of genes known to regulate joint development. This work revealed the precise changes to shape, particularly in the distal femur, that occur in an altered mechanical environment, corresponding to predicted changes in the spatial and dynamic patterns of mechanical stimuli and region specific changes in cell proliferation rates. In addition, we show altered patterning of the emerging tissues of the joint interzone with the loss of clearly defined and organised cell territories revealed by loss of characteristic interzone gene expression and abnormal expression of cartilage markers. This work shows that local dynamic patterns of biophysical stimuli generated from muscle contractions in the embryo act as a source of positional information guiding patterning and morphogenesis of the developing knee joint.     

Proximal versus distal control of two-joint planar reaching movements in the presence of neuromuscular noise

Determining how the human nervous system contends with neuro-motor noise is vital to understanding how humans achieve accurate goal-directed movements. Experimentally, people learning skilled tasks tend to reduce variability in distal joint movements more than in proximal joint movements. This suggests that they might be imposing greater control over distal joints than proximal joints. However, the reasons for this remain unclear, largely because it is not experimentally possible to directly manipulate either the noise or the control at each joint independently. Therefore, this study used a 2 degree-of-freedom torque driven arm model to determine how different combinations of noise and/or control independently applied at each joint affected the reaching accuracy and the total work required to make the movement. Signal-dependent noise was simultaneously and independently added to the shoulder and elbow torques to induce endpoint errors during planar reaching. Feedback control was then applied, independently and jointly, at each joint to reduce endpoint error due to the added neuromuscular noise. Movement direction and the inertia distribution along the arm were varied to quantify how these biomechanical variations affected the system performance. Endpoint error and total net work were computed as dependent measures. When each joint was independently subjected to noise in the absence of control, endpoint errors were more sensitive to distal (elbow) noise than to proximal (shoulder) noise for nearly all combinations of reaching direction and inertia ratio. The effects of distal noise on endpoint errors were more pronounced when inertia was distributed more toward the forearm. In contrast, the total net work decreased as mass was shifted to the upper arm for reaching movements in all directions. When noise was present at both joints and joint control was implemented, controlling the distal joint alone reduced endpoint errors more than controlling the proximal joint alone for nearly all combinations of reaching direction and inertia ratio. Applying control only at the distal joint was more effective at reducing endpoint errors when more of the mass was more proximally distributed. Likewise, controlling the distal joint alone required less total net work than controlling the proximal joint alone for nearly all combinations of reaching distance and inertia ratio. It is more efficient to reduce endpoint error and energetic cost by selectively applying control to reduce variability in the distal joint than the proximal joint. The reasons for this arise from the biomechanical configuration of the arm itself.     

Motion analysis of leg joints associated with escape turns of the cockroach,Periplaneta americana

Considerable information is now available on the neural organization of the escape system of the American cockroach. To relate these data to the behavior, we need detailed information on the movements made at the principle leg joints that produce the turn. We used motion analysis of high speed video records to acquire such information. Records from both free ranging and tethered animals were analyzed. 1. We analyzed individual joint movements using a tethered preparation. Stimuli from 4 different angles around the animal were used. For all wind angles, the femur-tibia (FT) joint on the mesothoracic leg that is ipsilateral to the wind source extended while the contralateral mesothoracic FT joint flexed. This moved both of these legs laterally toward the wind source. In freely moving animals the FT movements provide forces that turn the animal away from the wind source. 2. The ipsilateral mesothoracic coxa-femur (CF) joint extended for all wind angles. The contralateral mesothoracic CF joint extended in response to most winds from the rear, but switched to flexion in response to wind from the side and front. As a result of these joint movements, rear wind resulted in rearward movements of the contralateral mesothoracic leg, while side and front wind resulted in more forward movements of that leg. 3. The CF and FT joints for both ipsilateral and contralateral metathoracic legs extended to wind from the rear and switched to flexion as the wind was placed at more anterior positions around the animal. In freely moving animals, extension of these joints would push the animal forward. Flexion would pull the animal backward. 4. Several of the joints showed correlations between rate of movement and initial joint angle. That is, joints that were already flexed at the onset of stimulation tended to move at a faster rate to a final position than joints that started at a more extended position. 5. Metathoracic FT and CF joints showed a high degree of positive correlation during the escape movements. Indeed, many curves showing movement of metathoracic FT and CF joints with time were virtually identical.     

Notch signaling relieves the joint-suppressive activity of Defective proventriculus in the Drosophila leg

Segmentation plays crucial roles during morphogenesis. Drosophila legs are divided into segments along the proximal-distal axis by flexible structures called joints. Notch signaling is necessary and sufficient to promote leg growth and joint formation, and is activated in distal cells of each segment in everting prepupal leg discs. The homeobox gene defective proventriculus (dve) is expressed in regions both proximal and distal to the intersegmental folds at 4 h after puparium formation (APF). Dve-expressing region partly overlaps with the Notch-activated region, and they become a complementary pattern at 6 h APF. Interestingly, dve mutant legs resulted in extra joint formation at the center of each tarsal segment, and the forced expression of dve caused a jointless phenotype. We present evidence that Dve suppresses the potential joint-forming activity, and that Notch signaling represses Dve expression to form joints.     

An intracortical microstimulation study of output organization in precentral cortex of awake primates.

We investigated the output organization of the forelimb control area in primate precentral cortex by using low-current (less than 30 microamperemeter) intracortical microstimulation (ICMS). Movement about a joint was selected as the index of response. Penetrations perpendicular to the cortical surface and deep into the rostral bank of the central sulcus were made in two awake unanesthetized monkeys (Macaca arctoides). Cortical areas were designated by the joint about which movements occurred. 1. ICMS loci which produced movements about finger joints were found to tightly cluster in a central zone, and were surrounded by loci controlling movement about the wrist. This wrist zone was in turn approximately encircled by an elbow zone, which itself was enclosed by a shoulder zone. 2. Appreciable overlap between these zones controlling movements about contiguous joints was observed. 3. The observations indicate a nested-ring organization of the forelimb output zones of precentral cortex, such that a cortical zone controlling movement of a more distal joint is partly encircled by the zone controlling a more proximal joint.     

胶原诱导型关节炎大鼠的关节影像学特点

目的旨在分析CIA X线片四肢关节的破坏特点,揭示CIA大鼠关节破坏的规律,为规范评分方案提供依据。方法采用П型胶原和弗氏完全佐剂皮下注射清洁级Wistar大鼠,造模成功（每批10只,共3次）后第35天行全身X线钼靶照片,以正常组作为对照、每只大鼠评价96块骨破坏（erosion）和100个关节间隙（joint space narrowing,JSN）;处死动物,取左前肢和右后肢近端第3足趾关节苏木素-伊红（HE）染色,评价中性粒细胞、淋巴细胞、浆细胞浸润、滑膜增生和软骨破坏的情况。结果造模成功后CIA大鼠关节出现明显的红肿,活动受限;HE病理显示,CIA关节存在明显的中性粒细胞、淋巴细胞和浆细胞浸润,滑膜增生,纤维组织增生,软骨破坏;X线片分析结果显示：①广泛性骨质疏松,边缘性骨质侵蚀,关节间隙狭窄或增宽,部分踝关节间隙消失,关节相互融合甚至骨性强直。②67%的骨出现erosion,JSN影响为78%,关节破坏以中、重度为主;③远端、近端趾间关节和踝关节发病率高,损害严重,掌趾关节发病率低,破坏较轻。④后肢关节破坏重于前肢（P〈0.01）,左右肢没有显著性差异（P〉0.05）。结论①滑膜是CIA炎症反应启动的主要病灶,与骨交界的滑膜和血管翳造成了CIA的骨质破坏;②CIA影像学表现关节破坏严重,以远端、近端趾间关节和踝关节为主,这些关节可作为评价破坏程度的选择。本研究对于深入CIA关节破坏的病因病理和进一步规范X线片评分方案具有一定意义。     

Joint surfaces of the carpometacarpal articulation of the thumb in man

With respect of height and width of the proximal joint surface of the macerated 1st metacarpal bone as well as of height of the left trapezium results significant minor values compared with bones of right extremities. The measurement datas of height and width of both joint surfaces at the left macerated specimens are less significant than at left humid preparations. With respect of height of the proximal articular surfaces of the right 1st metacarpal bone, there are greater values than at the cartilageneous preparations by statistical significance. At macerated and humid preparated articulation surfaces of the saddle moint of the thumb there are 3 typical profiles in the 2 main planes: a spiral curve (vaulted in the dorsal or ulnar direction), a circular curve, and a s-shaped curve. The radius of the curve will be determined with adaptation of defined curve patterns. At the distal joint surface of the macerated trapezium, the circularly and spirally curved profiles are significantly much more crooked in the dorso-palmar direction than at the cartilageneous articulation surface on the contrary. The humid preparated distal joint surface of the trapezium in the radio-ulnar direction is clearly much more curved. The spiral form is found in 52,6% of all macerated and in 41,6% of all humid preparated specimens. The s-shaped profile is very rarely found at macerated joints (8%), whereas it appears in 26% at humid preparated surfaces. Corresponding cartilageneous saddle joints of the thumb are even similarly curved in 47% of the radio-ulnar and 40,5% of the dorso-palmar joints slices. The clear majority of the opposite carpometacarpal joint surfaces of the thumb show an individually variabel, partly an incongruent curving attitude. If different profiles at corresponding humid preparated joint surfaces assemble the following curvatures prevail: a) In the radio-ulnar cutting direction the combination: circular curve of the distal joint surface of the trapezium and spiral curve of the proximal surface of the 1st metacarpal bone, b) in the dorso-palmar direction: the combination spiral curve of the distal surface of the trapezium and circular curve of the 1st metacarpal bone.     

The mechanical environment of chondrocytes in articular cartilage

There is a growing literature concerning chondrocyte responses to mechanical loading, but relatively little is known about the mechanical environment these cells experience in a living joint. Calculations indicate that high forces are applied to limb joints whenever the joints are flexed, because flexion can cause body weight to act on long lever arms compared to the joint centre, whereas the muscles which extend the joint act on much shorter lever arms. As a result, joint reaction forces (which compress the cartilage) can rise to 3-6 times body weight during activities such as stair climbing. Articular cartilage tends to spread this load evenly over the joint surface, but is too thin to do this well, and compressive stresses can rise to 10-20 MPa. Within cartilage, matrix stresses vary locally, possibly as a result of variation in composition or undulations in the subchondral bone, and further modifications of stress occur within each chondron. Articular cartilage is a fibrous solid and cells within it are deformed by mechanical loading rather than subjected to a hydrostatic pressure. The mechanical environment of chondrocytes can best be reproduced in vitro by direct compression of the articular surface of cartilage which is supported naturally by adjacent cartilage and subchondral bone.     

Shape of articular surface of crocodilian (Archosauria) elbow joints and its relevance to sauropsids

The determination of area and shape of articular surfaces on the limb bones of extinct archosaurs is difficult because of postmortem decomposition of the fibrous tissue and articular cartilages that provide the complex three‐dimensional joint surfaces in vivo. This study aims at describing the shape of the articular cartilages in the elbow joints of six crocodilian specimens; comparing its structure with that of four birds, three testudines, and five squamates; and comparing the shapes of the surfaces of the calcified and the articular cartilages in the elbow joints of an Alligator specimen. The shapes of the articular cartilages of crocodilian elbow joint are shown to resemble those of birds. The humerus possesses an olecranon fossa positioned approximately at the midportion of the distal epiphysis and bordering the margin of the extensor side of the articular surface. The ulna possesses a prominent intercotylar process at approximately the middle of its articular surface, and splits the surface into the radial and ulnar cotylae. This divides the articular cartilage into an articular surface on the flexor portion, and the olecranon on the extensor portion. The intercotylar process fits into the olecranon fossa to restrict elbow joint extension. Dinosaurs and pterosaurs, phylogenetically bracketed by Crocodylia and Aves (birds), may have possessed a similar olecranon fossa and intercotylar process on their articular cartilages. Although these shapes are rarely recognizable on the bones, their impressions on the surfaces of the calcified cartilages provide an important indication of the extensor margin of the articular surfaces. This, in turn, helps to determine the maximum angle of extension of the elbow joint in archosaurs. J. Morphol., 2010. © 2010 Wiley‐Liss, Inc.     

Three-dimensional kinematic analysis of influence of hand orientation and joint limits on the control of arm postures and movements

The problems related to kinematic redundancy in both task and joint space were investigated for arm prehension movements in this paper. After a detailed analysis of kinematic redundancy of the arm, it is shown that the redundancy problem is ill posed only for the control of hand orientation. An experiment was then designed to investigate the influence of hand orientation on the control of arm movements. Since movements must be made within the limits of the joints, the influence of these limits was also analyzed quantitatively. The results of the experiment confirm that the increase of movement time because of the change of object orientation is due to the lengthening of the deceleration phase disproportionately to the rest of the movement. The variation of hand path due to the change of object orientation was observed as being surprisingly small for some subjects as opposed to the large range of object orientation, implying that hand path and hand orientation could be controlled separately, thus simplifying the computational problem of inverse kinematics. Moreover, the observations from the present experiment strongly suggest that a functional segmentation of the proximal and distal joints exists and that the control of wrist motion is dissociated from the rest of joint motions. The contribution of each joint in the control of arm movements could be determined through the principle of minimum energy and minimum discomfort under the constraints of the joint limits. A simplified inverse kinematics model was tested. It shows that these hypotheses can be easily implemented in a geometric algorithm and be used to predict arm prehension postures reasonably well under the constraints of joint limits. Received: 6 August 1998 / Accepted in revised form: 16 December 1998     

Temporal Control and Hand Movement Efficiency in Skilled Music Performance

Skilled piano performance requires considerable movement control to accomplish the high levels of timing and force precision common among professional musicians, who acquire piano technique over decades of practice. Finger movement efficiency in particular is an important factor when pianists perform at very fast tempi. We document the finger movement kinematics of highly skilled pianists as they performed a five-finger melody at very fast tempi. A three-dimensional motion-capture system tracked the movements of finger joints, the hand, and the forearm of twelve pianists who performed on a digital piano at successively faster tempi (7–16 tones/s) until they decided to stop. Joint angle trajectories computed for all adjacent finger phalanges, the hand, and the forearm (wrist angle) indicated that the metacarpophalangeal joint contributed most to the vertical fingertip motion while the proximal and distal interphalangeal joints moved slightly opposite to the movement goal (finger extension). An efficiency measure of the combined finger joint angles corresponded to the temporal accuracy and precision of the pianists’ performances: Pianists with more efficient keystroke movements showed higher precision in timing and force measures. Keystroke efficiency and individual joint contributions remained stable across tempo conditions. Individual differences among pianists supported the view that keystroke efficiency is required for successful fast performance.     

Form and function in lacertilian knee and mesotarsal joints; a contribution to the analysis of sprawling locomotion

The structure and function of the knee and mesotarsal (ankle) joints in lizards with normally developed limbs is described. It is shown that the knee joint is strictly of the hinge type, but is asymmetrical, resulting in a mesial inflexion of the long axis of the crus relative to that of the femur. The mesotarsal joint is a complex screw joint which permits conjunct rotatory movements of the crus on the pes, as well as flexion-extension. These movements are mediated by interlocking control surfaces on either side of the joint, and are an external expression of the geometry of these surfaces. The morphology of these joints, and the movements they permit are evaluated with reference to the movements of the limb segments during retraction.     

Determining finger segmental centers of rotation in flexion-extension based on surface marker measurement

This paper describes the development of a novel algorithm for deriving finger segmental center of rotation (COR) locations during flexion-extension from measured surface marker motions in vivo. The algorithm employs an optimization routine minimizing the time-variance of the internal link lengths, and incorporates an empirically quantifiable relationship between the local movement of a surface marker around a joint (termed "surface marker excursion") and the joint flexion-extension. The latter relationship constrains and simplifies the optimization routine to make it computationally tractable. To empirically investigate this relationship and test the proposed algorithm, an experiment was conducted, in which hand cylinder-grasping movements were performed by 24 subjects (12 males and 12 females). Spherical retro-reflective markers were placed at various surface landmarks on the dorsal aspect of each subject's right (grasping) hand, and were measured during the movements by an opto-electronic system. Analysis of experimental data revealed a highly linear relationship between the "surface marker excursion" and the marker-defined flexion-extension angle: the average R(2) in linear regression ranged from 0.89 to 0.97. The algorithm successfully determined the CORs of the distal interphalangeal, proximal interphalangeal, and metacarpophalangeal joints of digits 2-5 during measured motions. The derived CORs appeared plausible as examined in terms of the physical locations relative to surface marker trajectories and the congruency across different joints and individuals.     

A chondral modeling theory revisited

The mechanical environment of limb joints constantly changes during growth due to growth-related changes in muscle and tendon lengths, long bone dimensions, and body mass. The size and shape of limb joint surfaces must therefore also change throughout post-natal development in order to maintain normal joint function. Frost's (1979, 1999) chondral modeling theory proposed that joint congruence is maintained in mammalian limbs throughout postnatal ontogeny because cartilage growth in articular regions is regulated in part by mechanical load. This paper incorporates recent findings concerning the distribution of stress in developing articular units, the response of chondrocytes to mechanically induced deformation, and the development of articular cartilage in order to expand upon Frost's chondral modeling theory. The theory presented here assumes that muscular contraction during post-natal locomotor development produces regional fluctuating, intermittent hydrostatic pressure within the articular cartilage of limb joints. The model also predicts that peak levels of hydrostatic pressure in articular cartilage increase between birth and adulthood. Finally, the chondral modeling theory proposes that the cell-cell and cell-extracellular matrix interactions within immature articular cartilage resulting from mechanically induced changes in hydrostatic pressure regulate the metabolic activity of chondrocytes. Site-specific rates of articular cartilage growth are therefore regulated in part by the magnitude, frequency, and orientation of prevailing loading vectors. The chondral modeling response maintains a normal kinematic pathway as the magnitude and direction of joint loads change throughout ontogeny. The chondral modeling theory also explains ontogenetic scaling patterns of limb joint curvature observed in mammals. The chondral modeling response is therefore an important physiological mechanism that maintains the match between skeletal structure, function, and locomotor performance throughout mammalian ontogeny and phylogeny.     

A three-dimensional analysis of finger and bow string movements during the release in archery

The aim of this paper was to examine finger and bow string movements during archery by investigating a top Austrian athlete (FITA score = 1233) under laboratory conditions. Maximum lateral bow string deflection and angular displacements for index, third, and ring fingers between the full draw position and the end of the release were quantified using a motion tracking system. Stepwise multiple regression analyses were used to determine whether bow string deflection and finger movements are predictive for scoring. Joint ranges of motion during the shot itself were large in the proximal and distal interphalangeal joints, and much smaller in the metacarpophalangeal joints. Contrary to our expectations, greater deflection leads to higher scores (R2 = .18, p < .001) and the distal interphalangeal joint of the third finger weakly predicts the deflection (R2 = .11, p < .014). More variability in the joint angles of the third finger was found in bad shots than in good shots. Findings in this study let presume that maximum lateral bow string deflection does not adversely affect the archer's performance.     

High affinity glycosaminoglycan and autoantigen interaction explains joint specificity in a mouse model of rheumatoid arthritis

In the K/BxN mouse model of rheumatoid arthritis, autoantibodies specific for glucose-6-phosphate isomerase (GPI) can transfer joint-specific inflammation to most strains of normal mice. Binding of GPI and autoantibody to the joint surface is a prerequisite for joint-specific inflammation. However, how GPI localizes to the joint remains unclear. We show that glycosaminoglycans (GAGs) are the high affinity (83 nm) joint receptors for GPI. The binding affinity and structural differences between mouse paw/ankle GAGs and elbows/knee GAGs correlated with the distal to proximal disease severity in these joints. We found that cartilage surface GPI binding was greatly reduced by either chondroitinase ABC or beta-glucuronidase treatment. We also identified several inhibitors that inhibit both GPI/GAG interaction and GPI enzymatic activities, which suggests that the GPI GAG-binding domain overlaps with the active site of GPI enzyme. Our studies raise the possibility that GAGs are the receptors for other autoantigens involved in joint-specific inflammatory responses.