Sustained Limb-Level Loading: A Ground Reaction Force Phenotype Common to Individuals at High Risk for and Those With Knee Osteoarthritis.

OBJECTIVE: The objective of this study was to compare the vertical (vGRF), anterior-posterior (apGRF), and medial-lateral (mlGRF) ground reaction force (GRF) profiles throughout the stance phase of gait (1) between individuals 6 to 12 months post-anterior cruciate ligament reconstruction (ACLR) and uninjured matched controls and (2) between ACLR and individuals with differing radiographic severities of knee osteoarthritis (KOA), defined as Kellgren and Lawrence (KL) grades KL2, KL3, and KL4. METHODS: A total of 196 participants were included in this retrospective cross-sectional analysis. Gait biomechanics were collected from individuals 6 to 12 months post-ACLR (n = 36), uninjured controls matched to the ACLR group (n = 36), and individuals with KL2 (n = 31), KL3 (n = 67), and KL4 osteoarthritis (OA) (n = 26). Between-group differences in vGRF, apGRF, and mlGRF were assessed in reference to the ACLR group throughout each percentage of stance phase using a functional linear model. RESULTS: The ACLR group demonstrated lower vGRF and apGRF in early and late stance compared to the uninjured controls, with large effects (Cohen's d range: 1.35-1.66). Conversely, the ACLR group exhibited greater vGRF (87%-90%; 4.88% body weight [BW]; d = 0.75) and apGRF (84%-94%; 2.41% BW; d = 0.79) than the KL2 group in a small portion of late stance. No differences in mlGRF profiles were observed between the ACLR and either the uninjured controls or the KL2 group. The magnitude of difference in GRF profiles between the ACLR and OA groups increased with OA disease severity. CONCLUSION: Individuals 6 to 12 months post-ACLR exhibit strikingly similar GRF profiles as individuals with KL2 KOA, suggesting both patient groups may benefit from targeted interventions to address aberrant GRF profiles.

Knee kinetics and the medial femoral cartilage cross-sectional area response to loading in indviduals with anterior cruciate ligament reconstruction.

BACKGROUND: Ultrasonography is capable of detecting morphological changes in femoral articular cartilage cross-sectional area in response to an acute bout of walking; yet, the response of femoral cartilage cross-sectional area varies between individuals. It is hypothesized that differences in joint kinetics may influence the response of cartilage to a standardized walking protocol. Therefore, the study purpose was to compare internal knee abduction and extension moments between individuals with anterior cruciate ligament reconstruction who demonstrate an acute increase, decrease, or unchanged medial femoral cross-sectional area response following 3000 steps. METHODS: The medial femoral cartilage in the anterior cruciate ligament reconstructed limb was assessed with ultrasonography before and immediately following 3000 steps of treadmill walking. Knee joint moments were calculated in the anterior cruciate ligament reconstructed limb and compared between groups throughout the stance phase of gait using linear regression and functional, mixed effects waveform analyses. FINDINGS: No associations between peak knee joint moments and the cross-sectional area response were observed. The group that demonstrated an acute cross-sectional area increase exhibited 1) lower knee abduction moments in early stance in comparison to the group that exhibited a decreased cross-sectional area response; and 2) greater knee extension moments in early stance in comparison to the group with an unchanged cross-sectional area response. INTERPRETATION: The propensity of femoral cartilage to acutely increase cross-sectional area in response to walking is consistent with less-dynamic knee abduction and knee extension moment profiles.

Changes in biomechanics, strength, physical function, and daily steps after extended-release corticosteroid injections in knee osteoarthritis: a responder analysis.

INTRODUCTION/OBJECTIVE: To determine changes in gait biomechanics, quadricep strength, physical function, and daily steps after an extended-release corticosteroid knee injection at 4 and 8 weeks post-injection in individuals with knee osteoarthritis as well as between responders and non-responders based on changes in self-reported knee function. METHOD: The single-arm, clinical trial included three study visits (baseline, 4 weeks, and 8 weeks post-injection), where participants received an extended-release corticosteroid injection following the baseline visit. Time-normalized vertical ground reaction force (vGRF), knee flexion angle (KFA), knee abduction moment (KAM), and knee extension moment (KEM) waveforms throughout stance were collected during gait biomechanical assessments. Participants also completed quadricep strength, physical function (chair-stand, stair-climb, 20-m fast-paced walk) testing, and free-living daily step assessment for 7 days following each visit. RESULTS: All participants demonstrated increased KFA excursion (i.e., greater knee extension angle at heel strike and KFA at toe-off), increased KEM during early stance, improved physical function (all p < 0.001), and increased quadricep strength at 4 and 8 weeks. KAM increased throughout most of stance at 4 and 8 weeks post-injection (p < 0.001) but appears to be driven by gait changes in non-responders. Non-responders demonstrated lesser vGRF during late stance and lesser KEM and KFA throughout stance compared to responders at baseline. CONCLUSIONS: Extended-release corticosteroid injections demonstrated short-term improvements in gait biomechanics, quadricep strength, and physical function for up to 4 weeks. However, non-responders demonstrated gait biomechanics associated with osteoarthritis progression prior to the corticosteroid injection, suggesting that non-responders demonstrate more deleterious gait biomechanics prior to corticosteroid injection. Key Points • Individuals with knee osteoarthritis who were treated with extended-release corticosteroid injections demonstrated improvements in gait biomechanics and physical function for 8 weeks. • Individuals with knee osteoarthritis, who walked with aberrant walking biomechanics before treatment, failed to respond to extended-release corticosteroid treatment. • Future research should determine the mechanisms contributing to the short-term changes in gait biomechanics and physical function such as reduced inflammation.

Worse Tibiofemoral Cartilage Composition Is Associated with Insufficient Gait Kinetics After ACL Reconstruction.

PURPOSE: Greater articular cartilage T1ρ magnetic resonance imaging relaxation times indicate less proteoglycan density and are linked to posttraumatic osteoarthritis development after anterior cruciate ligament reconstruction (ACLR). Although changes in T1ρ relaxation times are associated with gait biomechanics, it is unclear if excessive or insufficient knee joint loading is linked to greater T1ρ relaxation times 12 months post-ACLR. The purpose of this study was to compare external knee adduction (KAM) and flexion (KFM) moments in individuals after ACLR with high versus low tibiofemoral T1ρ relaxation profiles and uninjured controls. METHODS: Gait biomechanics were collected in 26 uninjured controls (50% females; age, 22 ± 4 yr; body mass index, 23.9 ± 2.8 kg·m -2 ) and 26 individuals after ACLR (50% females; age, 22 ± 4 yr; body mass index, 24.2 ± 3.5 kg·m -2 ) at 6 and 12 months post-ACLR. ACLR-T1ρ High ( n = 9) and ACLR-T1ρ Low ( n = 17) groups were created based on 12-month post-ACLR T1ρ relaxation times using a k-means cluster analysis. Functional analyses of variance were used to compare KAM and KFM. RESULTS: ACLR-T1ρ High exhibited lesser KAM than ACLR-T1ρ Low and uninjured controls 6 months post-ACLR. ACLR-T1ρ Low exhibited greater KAM than uninjured controls 6 and 12 months post-ACLR. KAM increased in ACLR-T1ρ High and decreased in ACLR-T1ρ Low between 6 and 12 months, both groups becoming more similar to uninjured controls. There were scant differences in KFM between ACLR-T1ρ High and ACLR-T1ρ Low 6 or 12 months post-ACLR, but both groups demonstrated lesser KFM compared with uninjured controls. CONCLUSIONS: Associations between worse T1ρ profiles and increases in KAM may be driven by the normalization of KAM in individuals who initially exhibit insufficient KAM 6 months post-ACLR.

Linking Gait Biomechanics and Daily Steps After ACL Reconstruction.

PURPOSE: Aberrant biomechanics and altered loading frequency are associated with poor knee joint health in osteoarthritis development. After anterior cruciate ligament reconstruction (ACLR), individuals demonstrate underloading (lesser vertical ground reaction force (vGRF)) with stiffened knee gait biomechanics (lesser knee extension moment (KEM) and knee flexion angle) and take fewer daily steps as early as 6 months after surgery. The purpose of this cross-sectional laboratory study is to compare gait biomechanics throughout stance between individuals 6-12 months after ACLR who take the lowest, moderate, and highest daily steps. METHODS: Individuals with primary, unilateral history of ACLR between the ages of 16 and 35 yr were included (n = 36, 47% females; age, 21 ± 5 yr; months since ACLR, 8 ± 2). Barefoot gait biomechanics of vGRF (body weight), KEM (body weight × height), and knee flexion angle during stance were collected and time normalized. Average daily steps were collected via a waist-mounted accelerometer in free-living settings over 7 d. Participants were separated into tertiles based on lowest daily steps (3326-6042 daily steps), moderate (6043-8198 daily steps), and highest (8199-12,680 daily steps). Biomechanical outcomes of the ACLR limb during stance were compared between daily step groups using functional waveform gait analyses. RESULTS: There were no significant differences in sex, body mass index, age, or gait speed between daily step groups. Individuals with the lowest daily steps walk with lesser vGRF and lesser KEM during weight acceptance, and lesser knee flexion angle throughout stance in the ACLR limb compared with individuals with highest and moderate daily steps. CONCLUSIONS: After ACLR, individuals who take the fewest daily steps also walk with lesser vGRF during weight acceptance and a stiffened knee strategy throughout stance. These results highlight complex interactions between joint loading parameters after ACLR.

Differences in Gait Biomechanics Between Adolescents and Young Adults With Anterior Cruciate Ligament Reconstruction.

CONTEXT: Adolescents and adults are treated similarly in rehabilitation and research despite differences in clinical recovery after anterior cruciate ligament reconstruction (ACLR). Aberrant gait is a clinical outcome associated with poor long-term health post-ACLR but has not been compared between adolescents and adults. OBJECTIVE: To compare gait biomechanical waveforms throughout stance between adolescents (<18 years old) and young adults (≥18 years old) post-ACLR. DESIGN: Case-control study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Adolescents (n = 13, girls = 77%, age = 16.7 ± 0.6 years, height = 1.7 ± 0.1 m, weight = 22.2 ± 3.7 kg/m2) were identified from a cross-sectional cohort assessing clinical outcomes 6 to 12 months post-ACLR. Young adults (n = 13, women = 77%, age = 22.3 ± 4.0 years, height = 1.7 ± 0.1 m, weight = 22.9 ± 3.3 kg/m2) were matched based on sex, time since surgery (±2 months), and body mass index (±3 kg/m2). INTERVENTION(S): Participants performed 5 gait trials at their habitual speed. MAIN OUTCOME MEASURE(S): Three-dimensional gait biomechanics and forces were collected. Vertical ground reaction force normalized to body weight (xBW), knee-flexion angle (°), knee-abduction moment (xBW × height), and knee-extension moment (BW × height) waveforms were calculated during the stance phase of gait (0%-100%). Habitual walking speed was compared using independent t tests. We used functional waveforms to compare gait biomechanics throughout stance with and without controlling for habitual walking speed by calculating mean differences between groups with 95% CIs. RESULTS: Adolescents walked with slower habitual speeds compared with adults (adolescents = 1.1 ± 0.1 m/s, adults = 1.3 ± 0.1 m/s, P < .001). When gait speed was not controlled, adolescents walked with less vertical ground reaction force (9%-15% of stance) and knee-abduction moment (12%-25% of stance) during early stance and less knee-extension moment during late stance (80%-99% of stance). Regardless of their habitual walking speed, adolescents walked with greater knee-flexion angle throughout most stances (0%-21% and 29%-100% of stance). CONCLUSIONS: Adolescents and adults demonstrated different gait patterns post-ACLR, suggesting that age may play a role in altered gait biomechanics.

Anterior knee pain independently alters landing and jumping biomechanics.

Background Biomechanical effects of anterior knee pain are difficult to distinguish from effects of other factors also related to knee injury (e.g., joint effusion). The purpose of this study was to evaluate independent effects of anterior knee pain on landing and jumping biomechanics. Methods Thirteen healthy participants performed a land and jump movement task, under three experimental conditions (pre-pain, pain, and post-pain), during one data collection session. One 1-ml injection of hypertonic saline into the infrapatellar fat pad was used to induce experimental anterior knee pain during the pain condition. Participant-perceived anterior knee pain was measured every 2 min throughout data collection. Landing and jumping biomechanics were measured and compared between the experimental conditions using a functional statistical approach. Findings The aforementioned injection increased mean participant-perceived anterior knee pain, from zero during the pre-pain condition to 2.6 ± 0.71 cm during the pain condition. Vertical ground reaction force, knee flexion angle, and internal knee extension moment decreased by approximately 0.100 body weights, 3°, and 0.010 Nm/body weight × body height, respectively, between the pre-pain and pain conditions. Conversely, hip flexion angle and internal hip extension moment increased by approximately 3° and 0.006 Nm/body weight × body height, respectively, between the pre-pain and pain conditions. Several biomechanical changes persisted after anterior knee pain abatement (the post-pain condition). Interpretation Anterior knee pain alters landing and jumping biomechanics, independent of other injury-related factors. These altered biomechanics likely change knee joint loading patterns and might increase risk for chronic knee joint injury and/or pathology.

Alterations of a serum marker of collagen X in growing children with osteogenesis imperfecta.

Abnormalities in the structure and/or processing of type I collagen cause osteogenesis imperfecta and result in bone fragility, abnormal bone growth and short stature. Type I collagen is expressed in the growth plate but the mechanisms by which abnormalities in collagen I contribute to growth plate dysfunction and growth retardation are unknown. The non-collagenous domain (NC1) of type X collagen (CXM) is released from the hypertrophic zone of active growth plates and is a marker for new endochondral bone formation. Serum CXM levels are strongly correlated with the rate of growth in healthy children. We hypothesized that CXM levels in children with OI would be abnormal when compared to normally growing children. Using participants from the Brittle Bone Disease Consortium Natural History Study we analyzed the distribution of CXM over the ages of 8 months to 40 years in 187 subjects with OI (89 type I and 98 types III/IV) as well as analyzed the relationship between growth velocity and CXM levels in a subset of 100 children <16 years old with OI (44 type I and 56 types III/IV). CXM levels in both control and OI children demonstrated a similar pattern of variation by age with higher levels in early life and puberty followed by a post-pubertal drop. However, there was greater variability within the OI cohort and the relationship with growth velocity was weaker. The ratio of CXM level to growth velocity was elevated in children with type III/IV OI compared to controls. These results suggest that the relationship between hypertrophic zone function and the end point of skeletal growth is disrupted in OI.

Nonlinear transverse cascade and two-dimensional magnetohydrodynamic subcritical turbulence in plane shear flows.

We find and investigate via numerical simulations self-sustained two-dimensional turbulence in a magnetohydrodynamic flow with a maximally simple configuration: plane, noninflectional (with a constant shear of velocity), and threaded by a parallel uniform background magnetic field. This flow is spectrally stable, so the turbulence is subcritical by nature and hence it can be energetically supported just by a transient growth mechanism due to shear flow non-normality. This mechanism appears to be essentially anisotropic in the spectral (wave-number) plane and operates mainly for spatial Fourier harmonics with streamwise wave numbers less than the ratio of flow shear to Alfvén speed, ky

Angular redistribution of nonlinear perturbations: a universal feature of nonuniform flows.

Classically, the net action of nonlinear turbulent processes is interpreted as either a direct or inverse cascade. However, in nonuniform/shear flows the dominant process is a nonlinear redistribution over wave number angle of perturbation spatial Fourier harmonics. We call this process a nonlinear transverse redistribution (NTR). This phenomenon is demonstrated for a simple two-dimensional constant shear (non-normal) flow by numerically simulating the nonlinear dynamics of coherent and stochastic vortical perturbations in the flow. NTR is a general feature of nonlinear processes that should manifest itself in nonuniform engineering, environmental, and astrophysical flows. The conventional characterization of turbulence in terms of direct and inverse cascades, which ignores NTR, appears to be misleading for shear flow turbulence. We focus on the action of nonlinear processes on the spectral energy. NTR redistributes perturbations over different quadrants of the wave number plane and the interplay of this nonlinear redistribution with linear phenomena becomes intricate: it can realize either positive or negative feedback. In the case of positive feedback, it repopulates the quadrants in wave number space where the shear flow induces linear transient growth.

Modification of osteoarthritis in the guinea pig with pulsed low-intensity ultrasound treatment.

OBJECTIVE: The Hartley guinea pig develops articular cartilage degeneration similar to that seen in idiopathic human osteoarthritis (OA). We investigated whether the application of pulsed low-intensity ultrasound (PLIUS) to the Hartley guinea pig joint would prevent or attenuate the progression of this degenerative process. METHODS: Treatment of male Hartley guinea pigs was initiated at the onset of degeneration (8 weeks of age) to assess the ability of PLIUS to prevent OA, or at a later age (12 months) to assess the degree to which PLIUS acted to attenuate the progression of established disease. PLIUS (30 mW/cm(2)) was applied to stifle joints for 20 min/day over periods ranging from 3 to 10 months, with contralateral limbs serving as controls. Joint cartilage histology was graded according to a modified Mankin scale to evaluate treatment effect. Immunohistochemical staining for interleukin-1 receptor antagonist (IL-1ra), matrix metalloproteinase (MMP)-3, MMP-13, and transforming growth factor (TGF)-beta1 was performed on the cartilage to evaluate patterns of expression of these proteins. RESULTS: PLIUS did not fully prevent cartilage degeneration in the prevention groups, but diminished the severity of the disease, with the treated joints showing markedly decreased surface irregularities and a much smaller degree of loss of matrix staining as compared to controls. PLIUS also attenuated disease progression in the groups with established disease, although to a somewhat lesser extent as compared to the prevention groups. Immunohistochemical staining demonstrated a markedly decreased degree of TGF-beta1 production in the PLIUS-treated joints. This indicates less active endogenous repair, consistent with the marked reduction in cartilage degradation. CONCLUSIONS: PLIUS exhibits the ability to attenuate the progression of cartilage degeneration in an animal model of idiopathic human OA. The effect was greater in the treatment of early, rather than established, degeneration.

Developmental basis for hind-limb loss in dolphins and origin of the cetacean bodyplan.

Among mammals, modern cetaceans (whales, dolphins, and porpoises) are unusual in the absence of hind limbs. However, cetacean embryos do initiate hind-limb bud development. In dolphins, the bud arrests and degenerates around the fifth gestational week. Initial limb outgrowth in amniotes is maintained by two signaling centers, the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA). Our data indicate that the cetacean hind-limb bud forms an AER and that this structure expresses Fgf8 initially, but that neither the AER nor Fgf8 expression is maintained. Moreover, Sonic hedgehog (Shh), which mediates the signaling activity of the ZPA, is absent from the dolphin hind-limb bud. We find that failure to establish a ZPA is associated with the absence of Hand2, an upstream regulator of Shh. Interpreting our results in the context of both the cetacean fossil record and the known functions of Shh suggests that reduction of Shh expression may have occurred approximately 41 million years ago and led to the loss of distal limb elements. The total loss of Shh expression may account for the further loss of hind-limb elements that occurred near the origin of the modern suborders of cetaceans approximately 34 million years ago. Integration of paleontological and developmental data suggests that hind-limb size was reduced by gradually operating microevolutionary changes. Long after locomotor function was totally lost, modulation of developmental control genes eliminated most of the hind-limb skeleton. Hence, macroevolutionary changes in gene expression did not drive the initial reduction in hind-limb size.

Overview of studies comparing human normal cartilage with minimal and advanced osteoarthritic cartilage.

A major area under study in the osteoarthritis (OA) research field is the characterization of specific molecular and biochemical changes that distinguish advanced diseased cartilage from less involved or normal tissue. This information is important to better define the pathogenic mechanisms that are operating during OA progression and to identify disease-specific markers. This review describes recent studies that have addressed changes in chondrocyte gene expression, proliferation, and apoptosis in "experimental" (more advanced OA cartilage) versus "control" (less involved or non-OA cartilage). Included is a comprehensive listing of recently published studies in this area with general findings. The review also includes a discussion of study design and the strengths and weaknesses of the various approaches. In addition, specific strategies to deal with some of the important issues are discussed. One particular model utilizing minimal and advanced OA cartilage obtained from the same patient is described in more detail.

Delayed behavioural aging and altered mortality in Drosophila beta integrin mutants.

The genetic basis for aging is being intensely investigated in a variety of model systems. Much of the focus in Drosophila has been on the molecular-genetic determinants of lifespan, whereas the molecular-genetic basis for age-related functional declines has been less vigorously explored. We evaluated behavioural aging and lifespan in flies harbouring loss-of-function mutations in myospheroid, the gene that encodes betaPS, a beta integrin. Integrins are adhesion molecules that regulate a number of cellular processes and developmental events. Their role in aging, however, has received limited attention. We report here that age-related declines in locomotor activity are ameliorated and that mean lifespan is increased in myospheroid mutants. The delayed functional senescence and altered mortality in myospheroid flies are independent of changes in body size, reproduction or stress resistance. Our data indicate that functional senescence and age-dependent mortality are influenced by beta integrins in Drosophila.

Odor-guided behavior in Drosophila requires calreticulin.

The efficient processing of olfactory information is crucial for many aspects of life in animals, including behavior in insects. While much is known about the organization of the insect olfactory system, comparatively little is understood about the molecules that support its function. To further elucidate the molecular basis of olfaction, we explored the role of the calcium-binding chaperone calreticulin in the behavioral response of Drosophila to aversive odorants. We show that avoidance of naturally aversive odorants is impaired in flies harboring mutations in Calreticulin. Calreticulin mutants have broad defects in odor avoidance without abnormalities in antennal responses to odorants, alterations in central nervous system structure, or deficits in overall locomotor abilities. Interestingly, Calreticulin mutants exhibit defects in behavioral responses to odorants at low strength, whereas responses to higher odorant concentrations are preserved in these animals. Our studies indicate that calreticulin plays a key role in olfactory system function, possibly by establishing its overall sensitivity to odorants.

Chaotic scattering and the magneto-Coulomb map.

A nonrelativistic classical electron scattering by a fixed ion in a uniform magnetic field is discussed. The system is nonintegrable, and there is chaotic scattering for a certain class of initial conditions. A two-dimensional discrete map is derived from the equation of motion. Our map exhibits four different types of motion by changing the parameters which characterize the initial condition. The fractal structure for certain observables is obtained. The width of the chaotic scattering region in the impact parameter is estimated numerically. We suggest a certain class of plasma environments where the chaotic scattering may have an important role.

Cartilage viability after repetitive loading: a preliminary report.

OBJECTIVE: To assess matrix changes and chondrocyte viability during static and continuous repetitive mechanical loading in mature bovine articular cartilage explants. METHODS: Cartilage explants were continuously loaded either statically or cyclically (0.5 Hz) for 1-72 h (max. stress 1 megapascal). Cell death was assessed using fluorescent probes and detection of DNA strand breakage characteristic of apoptosis. Cell morphology and matrix integrity were evaluated using histology and transmission electron microscopy. RESULTS: Repetitive loading of articular cartilage at physiological levels of stress (1 megapascal) was found to be harmful to only the chondrocytes in the superficial tangential zone (STZ) and depended on the characteristics (static vs cyclic) and duration (1-72 h) of the applied load. The chondrocytes in the middle and deep zone remained viable at all times. Static loads caused cell death at an early time (3 h) as compared with cyclic loads (sinusoidal, 0.5 cycles per s for 6 h). The amount and extent of cell death peaked at 6 h of cyclic loading, and did not change in subsequent experiments run for longer periods of time (up to 72 h). There was no indication of fragmented nuclear DNA but there was evidence of injurious cell death (necrosis) by electron microscopy. Morphological analysis of cartilage repetitively loaded for 24 h showed matrix damage only in the uppermost superficial layer at the articular surface, reminiscent of the early stages of osteoarthritis. CONCLUSIONS: Cell death in mature cartilage explants occurred after 6 hours of continuous repetitive load or 3 h of static load. Cell death was directly related to the mechanical load, as control (free-swelling) explants remained viable at all times. The excessive, repetitive loading conditions imposed are not physiological, and demonstrate the deleterious effects of mechanical overload resulting in morphological and cellular damage similar to that seen in degenerative joint disease.

Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia.

Mutations in the cartilage oligomeric matrix protein (COMP) gene result in pseudoachondroplasia (PSACH), which is a chondrodysplasia characterized by early-onset osteoarthritis and short stature. COMP is a secreted pentameric glycoprotein that belongs to the thrombospondin family of proteins. We have identified a novel missense mutation which substitutes a glycine for an aspartic acid residue in the thrombospondin (TSP) type 3 calcium-binding domain of COMP in a patient diagnosed with PSACH. Immunohistochemistry and immunoelectron microscopy both show abnormal retention of COMP within characteristically enlarged rER inclusions of PSACH chondrocytes, as well as retention of fibromodulin, decorin and types IX, XI and XII collagen. Aggrecan and types II and VI collagen were not retained intracellularly within the same cells. In addition to selective extracellular matrix components, the chaperones HSP47, protein disulfide isomerase (PDI) and calnexin were localized at elevated levels within the rER vesicles of PSACH chondrocytes, suggesting that they may play a role in the cellular retention of mutant COMP molecules. Whether the aberrant rER inclusions in PSACH chondrocytes are a direct consequence of chaperone-mediated retention of mutant COMP or are otherwise due to selective intracellular protein interactions, which may in turn lead to aggregation within the rER, is unclear. However, our data demonstrate that retention of mutant COMP molecules results in the selective retention of ECM molecules and molecular chaperones, indicating the existence of distinct secretory pathways or ER-sorting mechanisms for matrix molecules, a process mediated by their association with various molecular chaperones.