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J Dent Res 82(9): 725-730, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Forward Mandibular Positioning Up-regulates SOX9 and Type II Collagen Expression in the Glenoid Fossa

A.B.M. Rabie1,*, T.T. She1, and V.R. Harley2

1 Hard tissue biology and repair research group and Orthodontics, Faculty of Dentistry, The University of Hong Kong, Prince Philip Dental Hospital, 34 Hospital Road, Hong Kong SAR, China; and
2 Prince Henry’s Institute, Melbourne, Australia;

* corresponding author, rabie{at}hkusua.hku.hk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Regulatory factors governing the formation of bone in the glenoid fossa in response to functional appliance therapy have not been identified. Therefore, the purpose of this study was to investigate the temporal pattern of expression of two key chondrogenesis markers—SOX9 and its target gene, type II collagen—in the glenoid fossa by immunostaining in a 35-day-old Sprague Dawley rat model during both natural growth and forward mandibular positioning. The expression of both factors was up-regulated when the mandible was positioned forward, indicating an enhancement of chondrocyte differentiation and chondroid matrix formation. Our results indicate that chondroid bone formation in the glenoid fossa in response to forward mandibular positioning is regulated by molecular markers indicative of endochondral ossification.

KEY WORDS: forward mandibular positioning • SOX9 • type II collagen • glenoid fossa


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chondroid bone in the glenoid fossa is a unique calcified tissue that possesses morphological and structural properties intermediate between those of cartilage and bone (Beresford, 1981). Morphologically, chondroid cells look similar to chondrocytes under light microscopy, although they are surrounded by a bone-like matrix. However, when the extracellular matrix is investigated structurally, it was shown to express not only components of cartilage, types II and X collagens, but also type I collagen and osteocalcin, which are the components of bone (Mizoguchi et al., 1997). A proposed mechanism for the formation of this kind of intermediate type of tissue is that chondroid cells transdifferentiate into either chondrocytes or osteoblasts, depending on the biomechanical environment (Silbermann et al., 1987; Strauss et al., 1990). In the field of orthodontics, functional appliance therapy is said to enhance the growth of glenoid fossa (Rabie et al., 2001) and condyles (Rabie et al., 2003), as a consequence of forward mandibular positioning. The mechanical strain produced by positioning the mandible forward induces growth of chondroid bone in the glenoid fossa (Rabie et al., 2001). However, the mechanism by which such bone is formed is not understood, and the regulatory factors governing its growth have not been identified.

SOX9 is a high-mobility group (HMG)-type transcription factor that is critical in the control of differentiation of the mesenchymal cells into chrondrocytes in long bone (Lefebvre and de Crombrugghe, 1998). SOX9 binds Col2a1/COL2A1 enhancer segments and activates gene expression of type II collagen (Lefebvre et al., 1997). Type II collagen is the main marker of the chondrocytes and forms the framework of cartilage matrix (Hall, 1983). Since type II collagen is expressed in the chondroid bone (Mizoguchi et al., 1997), it can be hypothesized that SOX9 is also expressed by the chondroid cells and that SOX9 expression regulates the differentiation of chondroid cells into chondrocytes.

Therefore, the purpose of this study was to investigate the temporal expression of SOX9 and type II collagen in the glenoid fossa during natural growth and during forward mandibular positioning induced by functional appliance therapy in an in vivo model. In so doing, we sought to gain a better understanding of how mechanical stimuli transmitted to the glenoid fossa by forward mandibular positioning can trigger the chondrocyte differentiation and chondroid matrix formation that eventually leads to growth modification of glenoid fossa.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
The animal model used in this study was the same as that described by Rabie et al. (2001). The animal protocol was reviewed and approved by the Committee on the Use of Live Animals in Teaching and Research, The University of Hong Kong (CULATR 481-00). Bite-jumping appliances that were fitted to the upper incisors of animals in the experimental group were worn 24 hrs a day, which produced a 3.5-mm anterior and 3-mm vertical opening of the mandible. The appliances were fabricated by cold-cure acrylic and cemented by means of PANAVIA-F® resin cement. No wear was observed on the appliance, since the inclined plane was made to come into contact with the lingual surfaces of the lower incisors.

Eighty female Sprague-Dawley rats (35 days old) were used in this study. They were randomly divided into experimental and control groups, with 5 in each group (n = 5).

The animals in both the experimental and control groups were fed with a soft diet. The animals in the experimental groups, together with their matched controls, were killed after 1, 3, 5, 7, 9, 11, 14, and 17 days, i.e., there were 8 experimental and control groups, respectively.

Tissue Preparation and Immunohistochemistry
The methods of tissue preparation and sectioning were the same as those described by Rabie et al. (2001), and the techniques of immunohistochemistry of SOX9 and type II collagen were discussed in detail by Rabie et al. (2003).

In brief, polyclonal rabbit anti-human SOX9 antibody raised against a Sox9 polypeptide, specific for the last 24 amino acids of full-length human Sox9 (Frojdman et al., 2000), was applied at a dilution of 1:100, which was localized in the sections by the application of biotin-conjugated goat-anti-rabbit IgG (Sigma B-8895, St. Louis, MO, USA), 1:200 pre-adsorbed with normal goat serum. Polyclonal goat anti-mouse collagen type II antibody (Santa Cruz Biotech. Sc-7763, Santa Cruz, CA, USA) 1:200 and biotin-conjugated rabbit-anti-goat IgG (Dako 0466, Carpinteria, CA, USA) 1:400, pre-adsorbed with normal rabbit serum, were used for the staining of type II collagen. Antibody reaction timing for the above-mentioned antibodies was standardized in 1 hr under 37°C.

The reaction products of the primary and secondary antibodies were visualized with an ABC kit (StreptABComplex/ HRP, DAKO Code No. K0377, Carpinteria, CA, USA) with DAB substrate (3,3-diaminobenzidine, Sigma D-5637, St. Louis, MO, USA) and were subsequently counter-stained with Mayer Haematoxylin.

Quantitative Analysis
The area of brown staining indicated that the expression of SOX9 and type II collagen in the posterior, middle, and anterior aspects of the glenoid fossa (Fig. 1Go) was measured by a true-color RGB (red-green-blue) computer-assisted image-analyzing system (Q550IW; Leica Microsystems Imaging Solutions, Cambridge, UK) and software (Leica Qwin Pro, V2.2; Leica Microsystems Imaging Solutions). This system acquires high-definition digital images of the specimen, and features from the acquired images are selected by the operator and recognized by color, shade, and contrast. The sections were evaluated at a total magnification of x360 (Leitz Orthoplan) under a fixed measurement frame of 298 mm2. We examined each section and confirmed it to be located consistently in the midsagittal plane by comparing the widths of the mandibular condyles. For each subject, 3 sections were quantified, and the mean of the measurements was used for statistical analysis. In total, 240 sections were measured and quantified. The amount of staining for all sections was quantified and evaluated by one examiner.



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  		Figure 1. Photomicrographs showing the expression of type II collagen at 38 days of natural growth in the anterior (A), middle (M), and posterior (P) regions of glenoid fossa (G), as well as the middle and posterior regions of the mandibular condyle (C), indicated by brown stains in the extracellular matrix of the hypertrophic layer (H) and in the chondrocytes.

 
The data were processed with SPSS® for Windows (Version 10.1, SPSS Inc.) for both t test and ANOVA.

Method Error
We calculated method error (ME) in measuring the areas of staining according to the formula:


where d is the difference between the 2 registrations of a pair and n is the number of double registrations.

Ten subjects with 30 sections were drawn randomly and were measured on 2 separate occasions approximately 1 month apart for method error analysis. A t test was also performed for comparison of inter-examiner agreement.

The method error (mm2) for the measurements of SOX9 and type II collagen was found to be 0.001 and 0.0007, respectively. p values were found to be larger than 0.05, indicating that there were no statistically significant differences between the 2 measurements.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Natural Growth
Expression of SOX9 was found to be localized in both the mesenchymal cells and hypertrophic chondrocytes (Fig. 2AGo), and the levels of expression of these 2 cell layers were pooled for quantitative analysis. In contrast, type II collagen was expressed intensively in the extracellular matrix of the hypertrophic layer and inside the chondrocytes of the glenoid fossa (Fig. 2CGo).



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  		Figure 2. Immunostaining of SOX9 and type II collagen in glenoid fossa. Photomicrographs showing the expression of SOX9 (A,B), indicated by brown stains, in proliferative (P) and hypertrophic (H) cells and type II collagen (C–F), indicated by brown stains of the chondrocytes and in the extracellular matrix (H). (A) Natural growth, day 38; (B) mandibular forward positioning, day 3 (38 days of natural growth); (C) natural growth, day 38; (D) mandibular advancement, day 3 (38 days of natural growth); (E) natural growth, day 52; and (F) mandibular forward positioning, day 17 (52 days of natural growth).

 
The expression of SOX9 and type II collagen in the anterior, middle, and posterior regions followed a similar pattern, with the maximum level of expression attained at day 38 of natural growth, followed by gradual reduction in expression until the end of the observation period (Figs. 3AGo, 3BGo). The exception was the expression of SOX9 in the middle region, where the maximum level of expression occurred on day 40 of natural growth (Appendix Tables A1, A2, www.dentalresearch.org).



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  		Figure 3. Graphs show the temporal patterns of expression of SOX9 and type II collagen in the anterior, middle, and posterior regions of the glenoid fossa during natural growth (A,B) and forward mandibular positioning (C,D). (A) Expression of SOX9 in the anterior, middle, and posterior regions during natural growth. (B) Expression of type II collagen in the anterior, middle, and posterior regions during natural growth. (C) Expression of SOX9 in the posterior region of the glenoid fossa during forward mandibular positioning and natural growth (n = 40). (D) Expression of type II collagen in the posterior region of the glenoid fossa during forward mandibular positioning and natural growth (n = 40). *p < 0.05; **p < 0.01; ***p < 0.0001.

 
Forward Mandibular Positioning
Forward mandibular positioning led to a significant increase in the expression of SOX9 and type II collagen at all time points in the anterior, middle, and posterior regions when compared with the expression of natural growth, except on experimental day 1 in all regions and day 7 in the middle and posterior regions for the expression of SOX9 and the middle region on experimental day 1 for type II collagen (Figs. 3CGo, 3DGo). The maximum level of expression was consistently found to be on experimental day 3 (day 38 of natural growth), with the percentage increase in the expression of SOX9 and type II collagen to be 71% and 55%, respectively, in the posterior region (Figs. 3CGo, 3DGo) (cf. Figs. 2AGo and 2BGo, 2CGo, 2DGo) (Appendix Tables A1, A2, www.dentalresearch.org). When the expression level during forward mandibular positioning was followed to the end of the experimental period, expression of SOX9 and type II collagen was significantly higher than natural growth (Figs. 3CGo, 3DGo) (cf. Figs. 2EGo, 2FGo).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Analysis of data from the present study showed that there is an increase in the amount of Sox9 expression, accompanied by an increase in the amount of type II collagen secreted in response to forward mandibular positioning (Figs. 3CGo, 3DGo). Such an increase could be due to the increased numbers of cells secreting Sox9 and type II collagen and/or to increased cellular activity. Currently, we are in the process of identifying cellular kinetics together with quantitative analysis of Sox9 mRNA to identify whether the cell numbers and/or cellular activity is increased during mandibular advancement. Such information would help us understand the mechanism by which these changes are triggered in response to forward mandibular positioning.

Earlier experimental models have generally supported results of the present study, where application of mechanical strain promoted chondrogenesis (Takahashi et al., 1998) and lack of mechanical strain caused failure of chondrogenesis (Fang and Hall, 1995). Paralyzed chicken embryos failed to form clavicles and limbs, which was associated with failure to activate chondrogenic markers, highlighting the prerequisite for physical movements in the initial stages of chondrogenesis (Hall and Herring, 1990). In contrast, upon the exertion of biomechanical forces in an in vitro system, chondrogenesis was promoted as a function of increase in cartilage molecular markers such as type II collagen and aggrecan and was associated with an up-regulation in Sox9 transcription factor, which is known to regulate both factors (Takahashi et al., 1998). It has been hypothesized by Voudouis et al. (2000) that when the mandible is positioned forward during functional appliance therapy, viscoelastic force was generated in the synovial fluid of the joint capsule through the connective tissue attachments of the articular disc complex and retrodiscal tissue. This force is transmitted onto the condyle and glenoid fossa, especially at the posterior region, and bone formation is induced. To identify the molecular events, we examined, in the present study, in an in vivo system, the temporal pattern of expression of type II collagen, the framework of the chondroid bone in the glenoid fossa, and the expression of SOX9, the positive regulator of chondrocyte differentiation and their synthesis of type II collagen (Hall, 1983; Lefebvre et al., 1997) during natural growth and during forward mandibular positioning.

Our study showed significant increases in the expression of SOX9 and type II collagen at all time points in the anterior, middle, and posterior regions during forward mandibular positioning when compared with that during natural growth (Figs. 3CGo, 3DGo) (Appendix Tables A1, A2, www.dentalresearch.org). The increase in SOX9 and type II collagen expression in the posterior region was 71% and 55% on experimental day 3 (day 38 of natural growth), respectively. These findings indicate an enhancement of chondrocyte differentiation and chondroid bone matrix formation in response to mechanical stimuli produced by forward mandibular positioning. These positive changes could be explained based on our earlier results as well as on results produced by several in vitro studies which have demonstrated that cartilage matrix synthesis is strongly influenced by mechanical stimuli (Lee and Bader, 1997; Torzilli et al., 1997). Biomechanical force produced by forward mandibular positioning changes the extracellular matrix (ECM), which, in turn, changes the shape of the non-differentiated mesenchymal cells present in the subperiosteal connective tissues in the glenoid fossa (Rabie et al., 2001). Changes in cell-cell interactions and/or cell-ECM interactions, through a transmembrane molecule such as the integrin, activate the mechanical signal transduction cascade, as it connects extracellularly to the collagen fibers and intracellularly to the cytoskeletal actin anchored to the nuclear membrane (Wang et al., 1993; Clark and Brugge, 1995). Distortion of the extracellular matrix can activate the mitogen-activated protein kinase and cAMP production through the integrin protein (Lee et al., 2000; Li et al., 2001). These pathways have been shown to up-regulate Sox9 gene expression and increase the DNA-binding capacity of SOX9 protein due to protein kinase A phosphorylation (Huang et al., 2000; Murakami et al., 2000). SOX9 then acts on the chondroid cells and induces their differentiation into chondrocytes. Furthermore, SOX9 has been shown to regulate the gene expression of type II collagen (Lefebvre et al., 1997). Therefore, the increase in the levels of expression of type II collagen in the glenoid fossa seen in the present study could be, in part, a result of the activation of the mechanical signal transduction cascade that up-regulated the gene expression of SOX9 and led to the increase in production of type II collagen (Fig. 4Go). The current results prompted us to ask why the glenoid fossa, an intramembranous bone of origin, would produce new bone through an endochondral route.



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  		Figure 4. Proposed model explaining how forward mandibular positioning could affect the gene expression of SOX9 and type II collagen.

 
Although bone formation in the glenoid fossa is reportedly intramembranous (Wright and Moffett, 1974), the growth of the chondroid bone layer is also highly responsive to mechanical stimuli which contribute to growth adaptation in response to masticatory function (Ten Cate, 1998). Kantomaa and co-workers measured the changes in growth of glenoid fossa and its articular eminence after feeding rats with a soft diet and shortening their incisors to reduce the loading of the glenoid fossa (Tuominen et al., 1996). They demonstrated the reduction in expression of type II collagen of the chondroid bone, especially on the posterior part of the glenoid fossa when subjected to reduced loading. In the current study, we showed that chondrocyte differentiation and type II collagen synthesis in the chondroid layer are enhanced in response to forward mandibular positioning. Based on our understanding of the nature of chondroid bone, we speculate that, under mechanical strain, chondroid cells differentiate first into chondrogenic cells which produce type II collagen, forming the framework of the chondroid matrix. The chondrocytes hypertrophy and differentiate into cells capable of producing a mineralized bone matrix (Roach, 1992) and eventually lead to bone formation.

In conclusion, biomechanical forces induced by forward mandibular positioning solicit molecular and cellular changes that lead to up-regulation in the expression of SOX9 and type II collagen in the glenoid fossa. These molecular changes improve our understanding of the tissue responses to functional appliance therapy.


   ACKNOWLEDGMENTS
 
This research was supported by CRCG grant 10203770.22311.08003.323.01 from the University of Hong Kong. A preliminary report was presented at the 78th European Orthodontic Society in the form of a poster presentation entitled "Chondrocyte differentiation and chondroid formation in the glenoid fossa during forward mandibular positioning".


   FOOTNOTES
 
A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org.

Received August 22, 2002; Last revision May 23, 2003; Accepted June 24, 2003


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