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PubMed1999

Down-regulation of chondrocyte aggrecan and type-II collagen gene expression correlates with increases in static compression magnitude and duration.

The goal of this study was to examine the simultaneous effects of mechanical compression of chondrocytes on mRNA expression and macromolecular synthesis of aggrecan and type-II collagen. Bovine cartilage explants were exposed to different magnitudes and durations of applied mechanical compression, and levels of aggrecan and type-IIa collagen mRNA normalized to glyceraldehyde-3-phosphate dehydrogenase were measured and quantified by Northern blot analysis. Synthesis of aggrecan and type-II collagen protein was measured by radiolabel incorporation of [35S]sulfate and [3H]proline into macromolecules. The results showed a dose-dependent decrease in mRNA levels for aggrecan and type-II collagen, with increasing compression relative to physiological cut thickness applied for 24 hours. Radiolabel incorporation into glycosaminoglycans and collagen also decreased with increasing compression in a dose-related manner similar to the changes seen in mRNA expression. The modulation of aggrecan and type-II collagen mRNA and protein synthesis were dependent on the duration of the compression. Aggrecan and type-II collagen mRNA expression increased during the initial 0.5 hours of static compression; however, 4-24 hours after compression was applied total mRNA levels had significantly decreased. The synthesis of aggrecan and collagen protein decreased more rapidly than did mRNA levels after the application of a step compression. Together, these results suggest that mechanical compression rapidly alters chondrocyte aggrecan and type-II collagen gene expression on application of load. However, our results indicate that the observed decreases in biosynthesis may not be related solely to changes in mRNA expression. The mechanisms by which mechanical forces affect different segments of the biosynthetic pathways remain to be determined.

Aggrecans↗
PubMed1982

Immune reactivity to native type II collagen in rheumatoid arthritis assessed by the leukocyte adherence inhibition assay and radioimmunoassay.

Cellular immunity to native type II collagen as well as to rheumatoid and osteoarthritic synovial membrane homogenates was assessed in a leukocyte adherence assay (LAI) in patients with rheumatoid arthritis (RA). Eleven out of 14 RA patients (79%) were positive in the LAI assay, demonstrating increased reactivity to rheumatoid over osteoarthritic synovial extracts. Increased reactivity to native type II collagen was not noted in the LAI assay. Radioimmunoassay studies demonstrated that 3 out of 14 RA patients (22%) had circulating IgG rheumatoid factor. None of the 11 patients with osteoarthritic or seronegative arthritis had antibodies to native type II collagen or circulating IgG rheumatoid factor, although 2 subjects with ankylosing spondylitis yielded positive LAI results. Our results suggest that type II collagen is not the important constituent in rheumatoid synovial membrane extract responsible for the positive LAI results observed in rheumatoid arthritis patients.

Arthritis, Rheumatoid↗
PubMed1983

Attenuation of an adjuvant arthritis by type II collagen.

Subcutaneous injection of the nonimmunogenic synthetic alkyldiamine, N,N-diotadecyl-N',N'-bis(2-hydroxyethyl) propanediamine (CP-20961), which possesses potent adjuvant properties for cellular sensitization, can induce an inflammatory arthritis in rats. To study whether a host reaction to native type II collagen plays a role in the pathogenesis of the arthritis in this model, CP-20961-injected Lewis rats received i.v. on four occasions native type II collagen coupled to syngeneic spleen cells with ethylcarbodiimide (CDI), native type II collagen added to spleen cells without CDI, or native type II collagen coupled to rat red blood cells (RBC) with glutaraldehyde. There was a significant suppression of the severity of arthritis in all three groups compared with a control group injected with CP-20961 but not receiving cells. In addition, the prevalence of arthritis was decreased in the group receiving native type II collagen-coupled RBC. Injection of cells coupled to denatured type II collagen, native type I collagen, and ovalbumin did not affect significantly the morphologic aspects of this disease. These data provide evidence that material possessing the quaternary epitope(s) of type II collagen functions in an as yet unidentified effector pathway in this adjuvant arthritis.

Animals↗
PubMed1998

Structurally abnormal type II collagen in a severe form of Kniest dysplasia caused by an exon 24 skipping mutation.

Type II collagen mutations have been identified in a phenotypic continuum of chondrodysplasias that range widely in clinical severity. They include achondrogenesis type II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia, Kniest dysplasia, and Stickler syndrome. We report here results that define the underlying genetic defect and consequent altered structure of assembled type II collagen in a neonatal lethal form of Kniest dysplasia. Electrophoresis of a cyanogen bromide (CNBr) (CB) digest of sternal cartilage revealed an alpha1(II)CB11 peptide doublet and a slightly retarded mobility for all major CB peptides, which implied post-translational overmodification. Further peptide mapping and sequence analysis of CB11 revealed equal amounts of a normal alpha1(II) sequence and a chain lacking the 18 residues (361-378 of the triple helical domain) corresponding to exon 24. Sequence analysis of an amplified genomic DNA fragment identified a G to A transition in the +5 position of the splice donor consensus sequence of intron 24 in one allele. Cartilage matrix analysis showed that the short alpha1(II) chain was present in collagen molecules that had become cross-linked into fibrils. Trypsin digestion of the pepsin-extracted native type II collagen selectively cleaved the normal length alpha1(II) chains within the exon 24 domain. These findings support a hypothesis that normal and short alpha-chains had combined to form heterotrimeric molecules in which the chains were in register in both directions from the deletion site, accommodated effectively by a loop out of the normal chain exon 24 domain. Such an accommodation, with potential overall shortening of the helical domain and hence misalignment of intermolecular relationships within fibrils, offers a common molecular mechanism by which a group of different mutations might act to produce the Kniest phenotype.

Amino Acid Sequence↗
PubMed1992

Transforming growth factor beta 1 stimulates type II collagen expression in cultured periosteum-derived cells.

Chondrogenesis can occur during a bone repair process, which is related to several growth factors. Transforming growth factor beta 1 (TGF-beta 1) downregulates the expression of type II collagen by chondrocytes in vitro, but injection of TGF-beta 1 into the periosteum in vivo increases type II collagen mRNA levels and initiates chondrogenesis. We examined the effect of TGF-beta 1 on collagen gene expression in a bovine periosteum-derived cell culture system to evaluate its direct effect on the periosteum. Cultured cells expressed alkaline phosphatase and collagen pro alpha 1(I) and pro alpha 1(II) mRNAs. A low level of type II collagen synthesis was demonstrated by immunoprecipitation. TGF-beta 1 had no effect on periosteal cell proliferation. Expression of collagen pro alpha 1(I) mRNA did not change with TGF-beta 1 treatment, but alkaline phosphatase mRNA showed a dose-dependent decrease. Expression of collagen pro alpha 1(II) mRNA was stimulated 2.7-fold by TGF-beta 1. TGF-beta 1 also caused a 2.6-fold increase in type II collagen synthesis by immunoprecipitation. These findings indicate that TGF-beta 1 is an enhancer of the expression of the chondrocyte phenotype of the periosteal cells and suggest that TGF-beta 1 is important in initiating and promoting cartilage formation in vivo.

Alkaline Phosphatase↗
PubMed1991

Effect of bucillamine (SA96) on type II collagen induced arthritis in rats.

The effects of bucillamine, a new antirheumatic drug, on type II collagen induced arthritis in rats was examined. Bucillamine inhibited hindpaw swelling in a dose dependent manner. The histopathological study indicated that bucillamine inhibited the proliferation of synovial lining cells. The anti-type II collagen antibody level was also decreased by the treatment with bucillamine. D-penicillamine, on the other hand, showed no beneficial effects on arthritis except for inhibiting new bone formation. Our findings suggest that bucillamine has beneficial effects on type II collagen induced arthritis in rats and that its mechanism of action is different from those of D-penicillamine.

Animals↗
PubMed1985

Influence of constituents of proteoglycans on type II collagen fibrillogenesis.

Turbimetry was used to study the influence of glycosaminoglycans of cartilage proteoglycans on type II collagen fibrillogenesis. The monosaccharides, D-glucuronate, N-acetyl-D-galactosamine, N-acetyl-D-glucosamine and D-galactose, all decreased the rate of the fibril formation. D-glucuronate had the strongest effect. The influence of chondroitin sulphate on type II collagen fibrillogenesis depended on the pH of the final solution, the length of the chondroitin sulphate chains and the concentration of chondroitin sulphate. At pH = 7.3 all chondroitin sulphate preparations decreased the rate of fibrillogenesis, while at pH = 6.9 and lower fibrillogenesis was stimulated by chondroitin sulphate (whale/shark), chondroitin 4-sulphate (whale) and chondroitin 6-sulphate (shark). The chain length of these three appeared to be longer than the chain length of chondroitin sulphate (human) and chondroitin sulphate oligosaccharides (whale/shark). At high concentrations (more than 3 mg/ml) fibril formation was less strongly retarded by keratan sulphate (human) than by chondroitin sulphate. At low concentrations a slight stimulation was observed in the presence of keratan sulphate. Glycosaminoglycans did not bind to collagen fibrils. At 0.5 mg/ml chondroitin 4-sulphate had a large solubilizing effect on fibrils compared to chondroitin 6-sulphate. Fibrillogenesis of type II collagen is in many aspects not comparable with fibrillogenesis of type I collagen.

Carbohydrates↗
PubMed1999

Suppression of collagen-induced arthritis by oral or nasal administration of type II collagen.

We directly compared the effects of oral and nasal administration of collagen type II (CII) on disease progression, cytokine production and T cell responses in DBA/1 mice. Lymphocytes were assayed for proliferation and cytokine production and cell lines established. T cells from fed or nasally treated groups proliferated significantly less and produced markedly less IFN-gamma than the non-fed immunized group 10 days after immunization and prior to onset of arthritis. T cell lines established from fed or nasally treated mice showed a pattern of cytokine production involving IL-4, IL-10 and TGF-beta, whereas T cell lines from the control group produced more IFN-gamma and IL-2. Suppression of clinical measures of arthritis was equivalent in the nasal and orally treated groups. Animals were then tested for IFN-gamma production 70 days after a booster immunization at a time when disease was apparent. Mucosally treated animals secreted less IFN-gamma as compared to controls, even at this late time point. Suppression of collagen induced arthritis (CIA) by nasal treatment of mice with CII was associated with diminished levels of TNF-alpha and IL-6 mRNA expression in the joints of tolerized mice, two cytokines known to be involved in the inflammatory and pathological process of CIA. These results demonstrate the induction of antigen specific Th2 and TGF-beta secreting regulatory cells following both oral and nasal treatment, which is associated with suppression of local inflammation in the joints and decreased Th1 type responses in the periphery throughout the course of the illness.

Administration, Intranasal↗
PubMed1994

[Serum antibodies to type II collagen and immune complex in cases of Menière's disease].

In a previous study, endolymphatic hydrops was induced in 36% of guinea pigs immunized with type II collagen and a dominant negative SP was recorded from these hydropic animals. These results suggested that the immune response to type II collagen may have a role in the etiopathology of some cases of Menière's disease. In this study, we evaluated the levels of serum antibody to type II collagen and three other immune indexes in patients with Menière's disease, especially those who showed negative SP dominance on electrocochleography. Twenty-nine Menière's cases, 22 normal volunteers serving as controls, 28 RA cases, and 9 patients complaining of vertigo were examined to detect serum immune indexes. Menière's patients exhibited high values of serum anti-type II collagen antibody as compared to control subjects. Furthermore, total IgG, C3, anti-type II collagen antibody and circulating immune complex were increased with the highest levels being in the RA group, followed by Menière's disease and then the control group. These results probably reflect the extent of immune reaction development. The immune response may be generalized in RA cases and/or local in Menière's disease. Our study results suggest the development of certain immune status abnormalities in our cases, which lends support to the idea of an immunologic disorder playing a role in the etiology of some cases of Menière's disease.

Adult↗
PubMed1992

The diagnostic significance of anti-type II collagen antibody assay in rheumatoid arthritis.

An improved enzyme-linked immunosorbent assay (ELISA) for the detection of anticollagen antibodies in human serum has been developed. With the use of this method, antibodies against native human Type II collagen were detected in 22.7% of sera from 480 patients with rheumatoid arthritis (RA). The antibodies were found to be collagen type specific, showing no reaction with human Type I and Type III collagens. The antibodies appeared in high incidence during the early phase of the disease, and RA patients with involvement of a single joint, mono-articular arthritis, were often positive for anti-Type II collagen antibodies. In most of these patients, anti-Type II collagen antibodies preceded the appearance of rheumatoid factors. The antibodies were all negative in sera from patients with gout, osteoarthritis (OA) and non-arthritic diseases. Thus, anti-Type II collagen antibody assay may have diagnostic significance for RA patients, especially those in whom laboratory and clinical findings provide only minimal help in diagnosis.

Adult↗
PubMed2006

[Distribution and expression of collagen type II, transforming growth factor beta1 and basic fibroblast growth factor in articular process cartilages of scoliosis].

OBJECTIVE: To look into the character of the expression of collagen type II and transforming growth factor beta1 (TGF-beta1), basic fibroblast growth factor (bFGF) in the apical articular process cartilages of adolescent idiopathic scoliosis (AIS) and congenital scoliosis (CS) patients. METHODS: The articular processes of 22 AIS and 18 CS were collected. The techniques of HE staining, immunohistochemistry and in situ hybridization were adopted in this research. By comparing the apical processes with the end processes, the convex processes with the concave processes, the AIS processes with CS processes, the pathological changes of the articular process cartilages of these patients and the distribution of collagen type II and TGF-beta1, bFGF in them were studied. The images of immunohistochemistry and in situ hybridization were input into the image analysis system and were analyzed semi-quantitatively. The SAS software (8.01) was adopted, and P < 0.05 was defined as the significant level. RESULTS: The expression of collagen type II and TGF-beta1, bFGF in AIS was similar to CS: the concave sides of apexes were higher than the convex sides. The comparisons had statistical significance. There was no statistical significance between upper and lower end vertebrae in convex and concave sides, between convex and concave sides in upper and lower end vertebrae. The apical vertebrae were significantly higher than the ipsilateral sides of upper or lower end vertebrae for collagen type II. There was no statistical difference of the expression at the concave, convex, upper, lower end vertebrae between AIS and CS. CONCLUSIONS: The cartilages of the apical processes show some signs of regression and hypoplasia in scoliosis. The concave side is more severe than the convex side. Increase of collagen type II and TGF-beta1, bFGF in the concave sides of apical processes in scoliosis may be the results of reconstruction of extracellular matrix and the compensation reactions which are caused by abnormal biomechanical forces such as compressive stresses. Compressive stress on the concave sides has more influences on the expression of collagen type II than tensile stress on the convex sides.

Adolescent↗
PubMed2005

Establishment of a simple and quantitative immunospot assay for detecting anti-type II collagen antibody using an infrared fluorescence imaging system (IFIS).

Antibodies to type II collagen (col II) have been detected in patients with rheumatoid arthritis and in animal models of collagen induced arthritis. Here, we describe a novel method to detect anti-col II antibodies using an immunospot assay with an infrared fluorescence imaging system. This method showed very high sensitivity and specificity, and was simple, with low background levels. It also showed higher reproducibility and linearity, with a dynamic range of approximately 500-fold, than the conventional immunospot assay with enhanced chemiluminescence detection. Using this method we were able to demonstrate the antibody affinity maturation process in mice immunized with col II. In these immunized mice, although cross-reactive antibodies reacting with other collagen species were detected in earlier stages of immunization, the titers of cross-reactive antibodies rapidly diminished after the antigen boost, concomitantly with the elevation of the anti-col II antibody. The method and its possible applications are discussed.

Animals↗
PubMed1996

Intracellular distribution of type II collagen mRNA and prolyl 4-hydroxylase in embryonic avian corneal epithelia.

BACKGROUND: The distribution of endoplasmic reticulum (ER) proteins and type II collagen mRNA in whole mount preparations of embryonic corneal epithelia was investigated. We asked, do transmission electron microscopy (TEM) and confocal microscopy of chick prolyl 4-hydroxylase (CPH) show similar ER distributions as CPH is necessary for collagen biosynthesis? METHODS: The overall distribution of ER was analyzed by TEM. Collagen secreting ER was localized with antibodies to chick prolyl 4-hydroxylase (CPH, CPH-alpha, or CPH-beta subunits). Type II collagen mRNA distribution was determined by in situ hybridization. RESULTS: The ER localized with TEM, and immunohistochemistry using anti-CPH antibodies, showed similar distribution patterns. Immunostaining for CPH and CPH-beta was prominent in both periderm and basal cells and also appeared to stain the periderm apical surface. CPH-alpha was less intense, only localizing to ER regions. The basal cell CPH distribution appeared perinuclear in optical sections that contained nuclei, but occupied nearly all the cytoplasm in a reticular pattern above and below nuclei, similar to that seen with TEM cross-sections. Epithelia double labeled with propidium iodide and CPH showed overlapping cytoplasmic staining. The distribution of type II collagen mRNA was similar to the ER staining pattern, appearing to represent a subset of total ER. CONCLUSIONS: This study demonstrates that ER markers have a similar distribution as type II collagen mRNA in embryonic avian corneal epithelia. In addition the CPH subunits had distinct, but overlapping distributions, suggesting that they may act independently.

Animals↗
PubMed1990

Etodolac preserves cartilage-specific phenotype in human chondrocytes: effects on type II collagen synthesis and associated mRNA levels.

We have shown that interleukin-1 (IL-1) suppresses expression of cartilage-specific types II and IX collagens by cultured human chondrocytes. This inhibition is potentiated by agents which block IL-1-stimulated PGE2 production (J. Clin. Invest. 82:2026, 1988). In contrast, expression of types I and III collagens and fibronectin, matrix components produced by chondrocytes that have lost cartilage-specific phenotype, is increased by IL-1, particularly when IL-1-stimulated synthesis of PGE2 is blocked by a prostaglandin synthetase inhibitor. Etodolac is a new NSAID which is an effective inhibitor of PGE2 synthesis. The enhanced potency of etodolac in chondrocytes (compared with macrophages) suggests that this drug may have selective effects on different target cell types. The present studies were undertaken to compare the effects of etodolac and other nonsteroidal anti-inflammatory drugs (NSAIDs) on IL-1-induced modulation of chondrocyte phenotype. Juvenile human costal chondrocytes or adult articular chondrocytes in primary culture were incubated with etodolac, indomethacin or ketoprofen in the absence or presence of IL-1 beta. After treatment the [3H] proline-labelled collagens were analyzed by SDS-PAGE and type I and type II collagen mRNAs were analyzed by Northern or dot hybridization. Indomethacin (0.3-300 nM) or ketoprofen (2-2000 nM) produced a dose-dependent suppression of type II collagen synthesis associated with decreased levels of type II collagen mRNA in the absence of IL-1, while they potentiated the inhibitory effects of IL-1. In contrast, etodolac (2-2000 nM) maintained expression of type II collagen protein and mRNA. Etodolac unmasked a stimulatory effect of IL-1 on synthesis of type I collagen and fibronectin and levels of type I collagen mRNA, but to a lesser extent than indomethacin. These results suggest that, despite equipotent inhibitory effects of etodolac (IC50 congruent to 10 nM) on PGE2 biosynthesis compared with indomethacin (IC50 congruent to 1.0 nM) or ketoprofen (IC50 congruent to 10 nM), etodolac may be capable of maintaining type II collagen expression by chondrocytes. In vivo this could help to prevent the detrimental effects of mediators such as IL-1 on cartilage matrix synthesis in inflammatory joint diseases.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

IgG subclasses of antibodies to type II collagen in rheumatoid arthritis differ from those in systemic lupus erythematosus and other connective tissue diseases.

OBJECTIVE: To compare IgG subclass distribution of autoantibodies to native type II collagen in patients with rheumatoid arthritis (RA) and in other rheumatic and inflammatory diseases including systemic lupus erythematosus (SLE). METHODS: The IgG subclass of antibodies to native type II collagen were measured by modified ELISA using chemiluminescent detection and subclass-specific monoclonal antibodies in sera that contained IgG antibodies to collagen using conventional ELISA. RESULTS: Antibodies to native type II collagen were present in sera of 20% of 323 patients with RA. 9% of 211 patients with SLE, 12% of 50 patients with osteoarthritis, and 13% of 75 patients with other chronic inflammatory diseases, but the highest levels occurred in patients with RA. The IgG subclass distribution of these antibodies differed markedly according to disease. In RA the predominant subclasses were IgG1 (58%) and IgG3 (47%), whereas in SLE the predominant subclass was IgG4 (69%). IgG2 was represented across all disease groups. Overall the frequency of IgG1 and/or IgG3 antibodies to type II collagen (84%) was significantly greater in RA than in other disease groups combined (20%) (p < 0.0001). CONCLUSION: Antibodies to native collagen in RA were predominantly of the complement fixing and potentially damaging subclasses IgG1 and IgG3, but in SLE were of the non-complement fixing subclass IgG4; in other diseases, where present, antibodies were mostly IgG2 and of low level. These observations support the importance of autoimmunity to collagen in the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed1993

Assembly of cartilage collagen fibrils is disrupted by overexpression of normal type II collagen in transgenic mice.

Cartilage collagen fibrils, which are characterized by their thin, uniform diameters, are formed of a multicomponent system of three collagen types (II, IX, and XI) and interacting proteoglycans. We have used a genetic approach to test whether the proper assembly of this multiprotein structure was altered by overexpression of one of its normal components. Here we show that in transgenic mice in which the normal mouse alpha 1(II) collagen is overexpressed, thick abnormal collagen fibrils are generated. Mice that showed the highest expression of the transgene also displayed a larger proportion of abnormal fibrils and died at birth. We propose that an imbalance among the constituents of the cartilage collagen fibrils disrupts the mechanism that controls their assembly. The results show the applicability of the transgenic mice system to studies of complex multicomponent protein assemblies in intact animals.

Animals↗
PubMed2005

Destructive effects of murine arthritogenic antibodies to type II collagen on cartilage explants in vitro.

Certain monoclonal antibodies (mAbs) to type II collagen (CII) induce arthritis in vivo after passive transfer and have adverse effects on chondrocyte cultures and inhibit self assembly of collagen fibrils in vitro. We have examined whether such mAbs have detrimental effects on pre-existing cartilage. Bovine cartilage explants were cultured over 21 days in the presence of two arthritogenic mAbs to CII (CIIC1 or M2139), a non-arthritogenic mAb to CII (CIIF4) or a control mAb (GAD6). Penetration of cartilage by mAb was determined by immunofluorescence on frozen sections and correlated with changes to the extracellular matrix and chondrocytes by morphometric analysis of sections stained with toluidine blue. The effects of mAbs on matrix components were examined by Fourier transform infrared microspectroscopy (FTIRM). A possible role of Fc-binding was investigated using F(ab)2 from CIIC1. All three mAbs to CII penetrated the cartilage explants and CIIC1 and M2139, but not CIIF4, had adverse effects that included proteoglycan loss correlating with mAb penetration, the later development in cultures of an abnormal superficial cellular layer, and an increased proportion of empty chondrons. FTIRM showed depletion and denaturation of CII at the explant surface in the presence of CIIC1 or M2139, which paralleled proteoglycan loss. The effects of F(ab)2 were greater than those of intact CIIC1. Our results indicate that mAbs to CII can adversely affect preformed cartilage, and that the specific epitope on CII recognised by the mAb determines both arthritogenicity in vivo and adverse effects in vitro. We conclude that antibodies to CII can have pathogenic effects that are independent of inflammatory mediators or Fc-binding.

Animals↗
PubMed1994

Retarded chondrogenesis in transgenic mice with a type II collagen defect results in fracture healing abnormalities.

We have examined the biological and biomechanical consequences of defective type II collagen production for fracture repair employing a genetically engineered mouse line Del1 which was generated by microinjection of a 39-kb mouse pro alpha 1(II) collagen gene construct containing a deletion of exon 7 and intron 7 (Metsäranta et al. [1992] J. Cell Biol. 118:203-212). Standardized tibial fractures were produced in transgenic Del1 mice and their nontransgenic littermates were used as controls. The fracture callus tissues were analyzed at days 7, 9, 14, 28, and 42 using radiography, histomorphometry, biomechanical testing, and Northern analysis of mRNAs for several tissue-specific matrix components. Deficient production of cartilage in Del1 mice resulted in reduced radiographic callus size, smaller cross-sectional area, and impaired biomechanical properties when compared with fractures of nontransgenic control mice. The differences were most evident in 14-day fracture calluses. Consequently mRNAs for cartilage-specific type IX and X collagens and aggrecan were also reduced in Del1 calluses. Levels of type II collagen mRNAs were unaffected since the mutated transgene produced additional type II collagen mRNA molecules. Further abnormalities in the fracture repair process of Del1 mice were observed in callus remodeling. In the control animals a typical feature of external callus remodeling was reduction of callus size during endochondral ossification between days 14 and 28. Such reduction was not observed in the transgenic mice. Histological examination of fracture calluses suggested also a reduction in trabecular surface area, which was found to be even more pronounced in metaphyseal bone of Del1 mice. Despite these differences the biomechanical properties of the calluses in the two groups became similar by day 28 of fracture healing. The results thus suggest that reduced chondrogenesis due to the presence of mutated transgenes in Del1 mice not only causes a temporary impairment in biomechanical properties of healing fractures but also affects later stages of callus remodeling.

Animals↗