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Arthritis Rheum. Author manuscript; available in PMC Mar 1, 2010.
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PMCID: PMC2724839



Chondrocytes are the sole cell type in articular cartilage and maintain the extracellular matrix through a homeostatic balance of anabolic and catabolic activities that are influenced by genetic factors, soluble mediators, and biophysical factors such as mechanical stress. Chondrocytes are encapsulated by a narrow tissue region termed the “pericellular matrix”, which in normal cartilage is defined by the exclusive presence of type VI collagen. Because the pericellular matrix completely surrounds each cell, it is hypothesized to serve as a filter or transducer for biochemical and/or biomechanical signals from the cartilage extracellular matrix. In this study, we used Col6a1−/− mice to investigate whether the lack of collagen VI may affect the development and biomechanical function of the pericellular matrix and alter the mechanical environment of the chondrocytes during joint loading. Col6a1−/− and Col6a1+/− mice possessed structurally intact pericellular matrices, but with significantly reduced mechanical properties as compared to wild-type controls. With age, Col6a1−/− showed accelerated development of osteoarthritic joint degeneration, as well as other musculoskeletal abnormalities such as delayed secondary ossification process and reduced bone mineral density. These findings suggest an important role for type VI collagen in regulating the physiology of the synovial joint, and provide indirect evidence that alterations in the mechanical environment of the chondrocytes, either due to loss of pericellular matrix properties or Col6α1−/− derived joint laxity, can lead to the progression of osteoarthritis.

Keywords: arthritis, collagen VI, proteoglycan, pericellular matrix, chondron, chondrocyte


Articular cartilage is the tissue that lines the surfaces of diarthrodial joints and serves as the resilient, low-friction, load-bearing material for joint motion. A sparse population of cells – chondrocytes - maintains the extracellular matrix (ECM) of this tissue through a balance of anabolic and catabolic activities. The micromechanical environment of chondrocytes, in conjunction with biochemical (e.g., growth factors, cytokines) and genetic factors, plays an important role in cartilage homeostasis and, as a consequence, the health of the joint (13). Chondrocytes in articular cartilage are enclosed by a narrow region of tissue, the pericellular matrix (PCM), which together with the enclosed chondrocyte has been termed the chondron (47). The PCM is primarily characterized by the exclusive presence of type VI collagen in normal cartilage, but it also possesses a high concentration of proteoglycans, fibronectin, and types II and IX collagen (4, 8).

The functional role of the PCM in articular cartilage is still unknown, although the fact that it completely surrounds the cell suggests that it regulates the biomechanical, biophysical, and biochemical signals that the chondrocyte perceives (9). For example, interactions between cell surface receptors and the ECM significantly influence matrix metabolism, gene expression, and response to growth factors (1012). Furthermore, cytokines and growth factors that interact with the chondrocyte surface traverse the pericellular environment, where they may be retained and modified (13, 14). From a biomechanical standpoint, there has been considerable speculation that the PCM plays a critical biomechanical role in either in protecting the cells or serving as a “filter” or transducer of physical signals in the ECM (6, 9, 1517), potentially through an interaction of type VI collagen with integrins or other cell surface receptors (1821). Indirect evidence in support of these hypotheses is provided by experimental data showing that a newly formed PCM augments cellular metabolic response to biomechanical loading (22).

Type VI collagen serves as the defining boundary of the PCM in articular cartilage, but it is also found in the ECM of many connective tissues (23). It has a characteristic beaded filamentous structure of tetrameric units that consists of three different α-chains, α1(VI), α2(VI), and α3(VI). Collagen VI has high affinity with numerous ECM components (i.e., biglycan, decorin, hyaluronan, fibronectin, perlecan, and heparin) as well as with the cell membrane (2428). Thus, it has been hypothesized that collagen VI plays important roles in mediating cell-matrix interactions as well as intermolecular interactions in various tissues as well as cell cultures (2933). In articular cartilage, collagen type VI forms a network that anchors the chondrocyte to the PCM (3437) through its interaction with hyaluronan (28, 38), decorin (25), and fibronectin (39).

The goal of this study was to examine the hypothesis that lack of type VI collagen alters the biomechanical properties of the PCM and ECM of articular cartilage. Collagen VI deficient mice were generated by targeted gene disruption of the Col6a1 gene (40). Histological analysis and dual energy x-ray absorptiometry (DXA) were used to examine differences in skeletal development, bone mineral density, and progression of osteoarthritic joint degeneration in wild-type and collagen VI deficient mice. In addition, micromechanical testing was performed on the articular cartilage and on isolated chondrons using microindentation and micropipette aspiration techniques, respectively to determine the role of type VI collagen on the elastic properties of the ECM and PCM of articular cartilage.

Materials and Methods

Collagen VI knockout mice

Collagen VI knockout mice were generated on a CD1 genetic background by targeted gene disruption of the Col6a1 gene, which is responsible for the production of α1(VI) chain (40). The elimination of the α1(VI) chain resulted in the absence of triple helical collagen VI molecules in the ECM (40). Mice were sacrificed at 1, 3, 6, and 11 months time points. All procedures had been approved by the Duke University Institutional Animal Care and Use Committee.

Fluorescence immunohistochemistry

Collagen VI immunostaining was performed using a polyclonal anti-collagen VI antibody raised against a peptide mapping near the amino terminus of murine α1(VI) chain (Santa Cruz Biotechnology, CA). Cryostat sections of the coronal plane were obtained from decalcified femoral heads of mice using standard histological methods.

Skeletal Staining

One-month-old mice were sacrificed, skinned, and eviscerated. Alcian blue and alizarin red were used to stain the cartilage and bone respectively using standard skeletal staining techniques.

Histological analysis and morphometric grading

Fixed cryostat sections were stained with Toluidine blue and Hematoxylin and Eosin (H&E) using standard histological techniques. Osteoarthritic and developmental changes were assessed using quantitative histomorphometric grading schemes on the femoral head of 60 mice at ages of 1, 3, 6, and 11 months (41, 42). Osteoarthritic grading was based on the sum score of surface fibrillation (0 to 4), toluidine blue intensity staining (0 to 3), and fibrocartilage presence (0 to 2), which was reported as percentage of the 0 to 9 scale where 0% corresponds to no histological signs of osteoarthritis and 100% corresponds to the most severe changes (grade 9). Specimens were classified as non-OA (score 0–1), mild OA (15), and severe OA (5 to 9).

For developmental changes, the histological grading scale was based on the presence of the growth plate and the extension of the secondary ossification center (42), which was graded from 0 to 5 (0 corresponded to normal 1-month-old mice and 5 corresponded to normal 11-month-old mice). The grading scale was based on the assessment of the percentage of the ossified area relative to the total area: cartilage with growth plate and no secondary ossification area present (grade 0), area of secondary ossification less than 10% (grade 1), area of secondary ossification more than 10% and less than 50% (grade 2), area of secondary ossification more than 50% and less than 90% (grade 3), area of secondary ossification more than 90% (grade 4), no presence of growth plate (grade 5). The secondary ossification was reported as a percentage of the 0 to 5 scale where 0% corresponds to grade 0 (no secondary ossification) and 100% corresponds to the fully developed femoral head (grade 5).

Bone Mineral Density

Dual energy X-ray absorptiometry (DXA, PIXImus, Lunar Corp, Madison, WI) was used for measuring bone mineral density (43). The mice were weighed and placed in supine position in the DXA unit and the whole body except the skull was measured. A total of 82 mice were analyzed at ages of 1, 3, 6, and 11 months.

Mechanical testing of articular cartilage

A total of 18 right hip joints from one-month-old mice (Col6a1−/−: n=7, Col6a1+/+: n=7, Col6a1+/−: n=4) were tested in indentation using an electromechanical test system (ELF 3200, EnduraTEC, Minnetonka, MN) instrumented with a low capacity load-cell (250g, Sensotec, Columbus, OH) and extensometer (1mm, Epsilon, Jackson, WY) (44). Plane-ended microindenters were machined from glass fibers (diameter: 110 µm, Thorlabs, Newton, NJ). A dual-angle camera system was used to optically align the indenter tip perpendicular to the cartilage surface (Fig. 8). After applying a tare load of 0.3 grams-force and allowing it to equilibrate, four consecutive indentation displacements (5 µm/step with a ramping speed of 1 µm/sec) were applied to the cartilage surface and allowed to equilibrate for 200 sec per step. The time, reaction force, and displacement data were collected throughout the test at 1 Hz. The equilibrium force vs. displacement curve was obtained from the linear region of the curve. After mechanical tests, the thickness of cartilage from the tissue surface to the calcified cartilage was measured at a site adjacent to the test site using routine histology (5 µm sections labeled with Safranin-O and fast green). The Young’s modulus of mouse cartilage was calculated using an elastic indentation model (45) with assumed Poisson’s ratio of 0.25 (44).

Mechanical testing of the pericellular matrix

Chondrons were mechanically isolated (n=93 from 26 donors) from the femoral articular cartilage of 1-month-old mice as described previously with a custom-built “microaspirator”, which applies suction pressure to the cartilage surface with a modified syringe (46). The micropipette aspiration technique (4749) was used to measure the mechanical properties of the PCM, as described previously (5052). With this technique, the surface of the PCM is aspirated into a glass micropipette (12 µm diameter) by the application of a series of controlled pressures up to 18 kPa, and the ensuing equilibrated aspiration length is measured using video microscopy (Fig. 8). The Young’s modulus of the PCM was determined using a theoretical model that represents the chondron as an elastic, compressible layer (i.e., PCM) overlying an elastic half-space (i.e., chondrocyte) (46).

Statistical analysis

Statistical analysis was performed using a multi factorial Analysis of Variance (ANOVA) setup in Statistica (StatSoft, Tulsa, OK, USA). Categorical predictors were considered only AGE (1, 3, 6, 9, and 11) and GENOTYPE (+/+, +/−, and −/−). We assumed those variable were able to predict 4 dependent measurements namely weight, OA score, BMD, and ossification score. Full factorial design revealed that both AGE, GENOTYPE and the AGE*GENOTYPE effects were significant contributors, and thus post hoc comparison was performed using the Fisher LSD method. AGE effects were significant for all 4 measurements as expected. GENOTYPE effects between Col6a1+/+ and Col6a1−/− were significant for all 4 measurements (Figure 3, Figure 4, and Figure 5). GENOTYPE effects between Col6a1+/+, Col6a1+/−, and Col6a1−/− were significant only for OA and ossification scores. AGE*GENOTYPE effects within the same age groups were not significant for OA. For ossification scored, significant difference was observed between Col6a1+/+ and Col6a1−/− at 3 months only. For BMD, a significant difference was observed between Col6a1+/+ and Col6a1−/− for all ages except for 1 month.

Figure 3
Lack of collagen VI results in delayed growth and ossification. (A–C) Toluidine blue staining of the femoral head of 3-month-old mice. (A) In the wild type mice, the secondary ossification process is almost complete by 3 months, while (B) Col6a1 ...
Figure 4
Lack of collagen VI results in age-related osteoarthritis in the hip. (A–C) Histological sections of the femoral cartilage of 11-month-old mice stained with hematoxylin-eosin revealed significant progression of osteoarthritis in the knockout mice ...
Figure 5
Bone mineral density of Col6a1+/+, Col6a1+/−, and Col6a1−/− mice, as measured by micro-DXA. Bone mineral density depended on age (p<0.001) and was significantly lower in mice that lack type VI collagen (p<0.001). ...


Histological Evaluation

Mice lacking collagen VI exhibited no apparent abnormalities and all animals survived until sacrifice at 11 months. Wild type and heterozygous mice showed extensive pericellular labeling for type VI collagen in the articular cartilage, whereas knockout mice revealed no presence of type VI collagen (Fig. 1). Intense labeling of type VI collagen was also observed in the growth plate of one-month-old wild type mice (Fig. 1a).

Figure 1
Immunostaining revealed the pericellular distribution of type VI collagen in the cartilage of one-month-old Col6a1+/+ and Col6a1+/− mice (panel A and B). Collagen VI was also abundant in the ossification area (A). No type VI collagen was present ...

Skeletal staining of bone and cartilage (Fig. 2) in one-month-old mice indicated that Col6a1−/− mice are smaller in size and exhibit a slower ossification process of the upper (Fig. 2 C,D) and lower (Fig. 2 E,F) extremities that the wild type counterparts. The smaller size was also consistent with a trend toward lower body weight of one month old Col6a1−/− mice (16.5±2.4 g) as compared to Col6a1+/+ mice (versus the 18.3±1.99 g) (p=0.11, two-tailed t-test).

Figure 2
Skeletal analysis of one-month-old Col6a1+/+ (A) and Col6a1−/− (B) mice using alcian blue (cartilage) and alizarin red (bone) staining. Homozygous mutants are smaller, with slower ossification progress in the upper (C–D) and lower ...

To better evaluate the developmental process, we measured the secondary ossification process of the femoral head (Fig. 3A–C). Col6a1−/− mice showed significantly delayed ossification at 3 months (grade 2.2±1.8) as compared to Col6a1+/+ mice (grade 4.1±0.2) (p<0.02) (Fig. 3D) (see also Materials and Methods for grading scale and statistical analysis). For the 3 months old mice, only one out of 6 Col6a1−/− mice showed ossification grade above 4, whereas 3 out of 3 Col6a1+/+ showed an ossification grade above or equal to 4. The ossification process was complete for all mice after the 6th month.

Semi-quantitative histological analysis of cartilage degeneration revealed significant age-dependent osteoarthritic changes in the Col6a1−/− mice. Osteoarthritic changes depended on age (p<0.001) and genotype (p<0.05) (Fig. 4). For the 6- to 11-month-old mice, only 2/12 of the Col6a1+/+, 3/7 of the Col6a1+/−, and 11/16 Col6a1−/− scored above 1 and are characterized with OA (either mild or severe, see Materials and Methods for grading scale). However, 0/12 of the Col6a1+/+, 0/7 of the Col6a1+/−, and just 2/16 Col6a1−/− scored above 5 and were characterized as exhibiting severe OA.

Bone Mineral Density

DXA revealed that wild type mice have significantly higher bone mineral density than the knockout counterparts at 3 and 6 months (p<0.001), although these differences were no longer present by 11 months (Fig. 5)

Mechanical properties of articular cartilage and PCM

The PCM exhibited linear elastic behavior, and the Young’s modulus of the PCM of chondrons isolated from Col6a1+/+ mice was significantly higher than those of heterozygous Col6a1+/− mice, which was further reduced in the knockout Col6a1−/− mice (Fig. 6C). Microindentation tests revealed no significant differences in the mechanical properties of the femoral head articular cartilage Col6a1+/+, Col6a1+/−, or Col6a1−/− mice (Fig. 6D).

Figure 6
Mechanical testing of articular cartilage and PCM. (A) A microindentation system comprised by a plane-ended glass indenter was employed to assess the mechanical properties of murine articular cartilage. (B) The micropipette aspiration technique was used ...


The findings of this study provide new evidence of significant musculoskeletal changes in Col6a1−/− mice. Primarily, our findings show that mice lacking collagen VI exhibit accelerated development of hip osteoarthritis, as well as a delayed secondary ossification process and lower bone mineral density. Lack of type VI collagen resulted in a loss of the stiffness (decreased modulus) of the PCM of the articular cartilage prior to any detectable histological changes. However, no differences in ECM properties were observed. These findings provide indirect evidence of a role for type VI collagen in regulating the physiology of the chondrocyte, potentially due to alterations in the biological and mechanical environment of the chondrocytes in articular cartilage due to changes in biomechanical properties of the PCM or due to increased joint laxity associated with a deficiency in type VI collagen.

The mechanical environment of the chondrocytes is one of several environmental factors that influence the normal balance between the synthesis and breakdown of articular cartilage and is an important factor in etiopathogenesis of osteoarthritis (13, 53, 54). Thus, changes in the mechanical interactions between the cell and ECM may have a significant influence on the regulatory response of the chondrocyte. While a biomechanical function for the PCM has long been hypothesized (5, 6, 9), there is growing evidence from both theoretical modeling and experimental studies that the PCM plays a significant role in regulating the biomechanical signals perceived by the chondrocyte (17, 55, 56). In normal cartilage, the mechanical properties of the PCM are relatively uniform with depth (57) but are significantly altered with osteoarthritis, exhibiting reduced stiffness and increased fluid permeability (46, 58). The PCM appears to function by providing a relatively uniform cellular microenvironment despite large inhomogeneities in local tissue strain (17, 59). Thus, a compromised PCM could significantly affect the mechanical environment of the chondrocytes in articular cartilage, leading to increased strain at the cellular level (56), which may affect catabolic responses at the level of single cells (60). In other tissues such as bone, however, the pericellular region (i.e., the glycocalyx) can serve as a strain amplifier by coupling fluid drag forces to the actin cytoskeleton within the processes of osteocytes (6163). In the present study, Col6a1−/− mice showed significantly reduced PCM stiffness at 1 month of age, preceding any histological or biomechanical changes in the overall articular cartilage. With age, these mice exhibited accelerated development of osteoarthritis. These findings provide indirect evidence that early alterations in the mechanical properties of the PCM are associated to the progression of osteoarthritis.

In normal articular cartilage, type VI collagen is exclusively present in the PCM and it has been characterized as a discrete marker of chondron anatomy (36). For this reason, it has been hypothesized that type VI collagen is necessary for providing the structural integrity and mechanical properties of the PCM. Contrary to our hypotheses, though, Col6a1−/− mice exhibited intact chondrons that could be isolated despite the lack of type VI collagen. This finding suggests that proteins other than collagen VI provide some of the structural integrity of cartilage PCM. Nonetheless, the Young’s modulus (stiffness) of the PCM of Col6a1−/− mice was dramatically decreased to nearly one-third of the wild-type controls indicating the important role of type VI collagen in the properties of the PCM.

An important issue that must be considered is the link between collagen VI deficiency and changes in muscle physiology displayed by Col6a1−/− mice (40). Such link has also been observed in humans, where mutations of collagen VI genes have been shown to play a causal role in two inherited disorders of muscle, Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD) (64, 65). It is possible that some features of UCMD, particularly joint laxity or predisposition to hip dislocation, may also contribute to the accelerated hip degeneration observed in Col6a1−/− mice. Since joint laxity and PCM mechanical alterations are both inheritably coupled in Col6a−/− mice and both lead to altered mechanical environment in chondrocytes, both factors can contribute to the development of OA. While the present study clearly shows an association between Col6a1 deficiency and OA, presumably via mechanical alterations caused by joint laxity or altered PCM properties, further studies aimed at developing and characterizing conditional or tissue-specific knockouts may be required to fully understand the mechanisms by which Col6a1 deficiency leads to OA. Nonetheless, our results are consistent with the hypothesized role of type VI collagen as an integrating molecule in the structure of cells and tissues; downregulation of collagen VI is associated with tissue laxity and wasting (e.g., Bethlem myopathy, UCMD, joint hyperlaxity), whereas collagen VI upregulation results in increased fibrosis and tissue stiffness (e.g., Bullous keratopathy, scleroderma) (40, 6673).

In our experiments we found no gross morphologic differences between wild type and collagen VI knockout chondrons other than reduced skeletal size of Col6a1−/− mice. Skeletal changes were apparent as a retardation of the developmental process until 11 months of age. During development, histogenesis of long bones occurs via endochondral ossification of cartilage tissue. During this process, chondrocytes in the epiphyseal plate differentiate into mature hypertrophic cells and finally are eliminated from the growth plate (74). The hypertrophic cell lacunae are invaded by vessels carrying mesenchymal and osteogenic cells that differentiate into osteoclasts and synthesize a bony matrix. A similar procedure, known as secondary ossification, takes place at the end of the bone where the formation of the bony epiphysis occurs. Our experimental results point to a slowing of secondary ossification changes and decreased bone mineral density in the Col6a1−/− mice. While there is no known direct mechanism coupling type VI collagen deficiency to endochondral ossification, type VI collagen may provide a scaffold for osteoblasts, preosteoblasts and chondrocytes to proceed to osteochondral ossification (75). In addition, type VI collagen has been linked to the early events of chondrocyte differentiation (76), to the regulation of mesenchymal cell proliferation in vitro (77), and to ECM stabilization during development (36). It has also been hypothesized that collagen VI is important for chondrocyte proliferation and hypertrophy in cartilage (36, 78, 79). These studies in conjunction with our observation of the ubiquitous presence of type VI collagen in the growth plate (Fig. 1A) support the hypothesis that collagen VI deficiency may delay cell differentiation and proliferation, resulting in delayed development and decreased bone formation. Interestingly, the COL6A1 gene was recently identified as the locus for ossification of the posterior longitudinal ligament of the spine (75) and has been also associated with increased systemic bone mineral density and diffuse idiopathic skeletal hyperostosis (80). These findings point to a role for collagen VI in diseases associated with high-bone-mass, consistent with the lower bone mineral density we observed in Col6a1−/− mice. While it is beyond the scope of the present study to analyze the mechanisms resulting in altered bone mineral density, these changes may also be biomechanical in origin, as collagen VI deficiency causes muscular dystrophy (40, 68), which can lead to abnormal mechanical loading regime of the musculoskeletal systems.

In this study, the role of an abnormal mechanical environment on chondrocytes was investigated by using collagen type VI knockout mice. Our findings suggest that collagen VI plays a major role in the mechanical properties of the PCM, and thus, the mechanical environment of the chondrocytes. Col6a1−/− mice showed accelerated development of osteoarthritis that may be “biomechanical” in nature, either via altered properties of the PCM or inheritable joint laxity. In addition, our findings provide direct evidence that collagen type VI might have a significant role on the osteochondral ossification process by modulating the chondrocyte and mesenchymal cell differentiation and proliferation activities. This model may provide a valuable tool to better understand how changes in the mechanical environment of the chondrocytes may lead to abnormal skeletal development and development of osteoarthritis.


The authors would like to thank Dr. David Birk for his important advice and Gregory Williams and Jason Perera for their assistance with the project. This study was supported by the National Institutes of Health grants AG15768, AR48182, AR48852, and AR50245, and by Telethon grant GGP04113.


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