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Rheumatology 2001; 40: 256-261
© 2001 British Society for Rheumatology

Increased cell proliferation and associated expression of PDGFRß causing hypercellularity in patellar tendinosis

C. G. Rolf, B. S. C. Fu, A. Pau, W. Wang and B. Chan

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. This study assessed cellularity in patellar tendinosis with respect to cell proliferation and the expression of platelet-derived growth factor receptor ß (PDGFRß).

Methods. Surgical samples were taken from 11 patients fulfilling criteria of patellar tendinosis and from 12 matched controls. Standard immunohistochemistry methods were used to detect expression of PDGFRß and proliferation cell nuclear antigen (PCNA). Results were analysed by computer-assisted microscopy. Tendon cells were isolated from nine tendinosis and eight control tissues for cell culture.

Results. Increased cellularity (P<0.001) was observed in tendinosis tissues compared with controls, and also a higher proliferative index (P<0.001). Increased expression of PDGFRß was demonstrated (P<0.001). Cultured tendinosis cells showed a higher proliferation rate than controls (P<0.001). This was maintained when the cells were cultured under various conditions of serum supplementation (P<0.01). Tendinosis cells also showed a higher proliferation rate (P<0.01) in medium containing 10 ng/ml PDGF.

Conclusion. Hypercellularity in patellar tendinosis is caused by increased cell proliferation and is associated with increased expression of PDGFRß.

KEY WORDS: Tendinosis, Hypercellularity, Patellar tendon, PCNA, PDGF receptor beta.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Tendinosis is a common chronic tendon disorder with unknown pathogenesis and causation [1–8]. The clinical manifestation is long-standing localized and activity-related pain and swelling, and similar entities are described in the patellar tendon [9–11], the Achilles tendon [1–3, 4, 7] and the rotator cuff of the shoulder [7]. The literature is not consistent in the terminology and definition of tendinosis. It is sometimes called chronic tendinitis, although there is no infiltration of inflammatory cells [2–5]. From the aetiological standpoint, tendinosis is often described as an overuse injury [6], although it occurs in many patients who do not perform vigorous physical activity [2]. Some authors regard the disorder as being degenerative [4, 7], although tendinosis can also be found in young people [2]. It is not known whether substages of tendinosis exist and whether it is an ongoing process or an end-stage. Consequently, there is no defined and consistent rationale in current methods of management.

Histopathological studies of tendinosis tissues characteristically demonstrate hypercellularity, hypervascularity, lack of inflammatory infiltrates, and disorganization and loosening of collagen fibrils [2, 3, 4, 8]. Another obvious alteration is an increase in the glycosaminoglycan content of the extracellular matrix [3, 7, 8].

Hypercellularity, one of the criteria for tendinosis, putatively resulting from the abnormal cellular activity associated with the condition, has not been demonstrated by objective measures. Neither has the activity of the ‘tendinosis cells’ been demonstrated. As some of the tendinosis cells appear morphologically different from tenocytes [3, 7, 8], their origin remains speculative, but it is possible that they are transformed tenocytes. Tenocytes normally respond to intrinsic and extrinsic signals upon injury by proliferating and synthesizing extracellular matrix [12], and by showing some morphological changes. However, their role in the pathogenesis of tendinosis remains unexplored.

The purpose of this study was to verify objectively the presence of hypercellularity and assess cell proliferation by analysing the expression of proliferation cell nuclear antigen (PCNA), a protein that appears only in proliferating cells [13,14] in human patellar tendinosis tissues and not in healthy controls. The relationship between cell proliferation and changes in cytokine responsiveness was further assessed by determination of the expression of platelet-derived growth factor receptor ß (PDGFRß), as the activation by platelet-derived growth factor ßß (PDGFBB) on the PDGFRß is a well-known trigger for fibroblastic cell proliferation [15]. In order to validate the influence of any alteration in PDGFRß, we also measured the expression level of PDGFBB.

To find out whether the cells retain their pathological characteristics in situ, we also prepared tendon cells from human tendinosis tissues and compared their proliferative ability with that of healthy tendon cells in an established cell culture system.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
All procedures were approved by the Human Research Ethics Committee of the Chinese University of Hong Kong.

Patients
All subjects and controls were recruited from the Department of Orthopaedics and Traumatology, Prince of Wales Hospital, Hong Kong. Tendinosis and control subjects were thoroughly informed about the procedures, and completed consent forms before the operation. There were 11 patients (nine males and two females) with unilateral tendinosis, and their average age was 31 yr (range 15–40). They all had a duration of symptoms of more than 6 months and fulfilled the clinical and radiological criteria for tendinosis [13, 14], but were otherwise healthy. They all participated in various recreational sports. They had undergone physiotherapy (range 3–8 months) and all had been treated with oral non-steroidal anti-inflammatory drugs (NSAIDs) over shorter periods. None of the patients had received local cortisone injections. The controls were 12 patients who underwent reconstruction of the anterior cruciate ligaments, using the patellar tendon as a healthy autograft. These comprised eight males and four females with an average age of 31 yr (range 16–38). None of them reported any history of anterior knee pain. All of these patients had used NSAIDs occasionally and had undergone physiotherapy during a preoperative planning session at least 6 months after the injury. They all participated in recreational sports.

Surgery for the tendinosis patients was performed and guided by clinical findings, including ultrasonography and/or magnetic resonance imaging. The macroscopically abnormal region was excised under open vizualization, and a piece of tissue measuring 0.5x1.5 cm was preserved for analysis. In the control subjects, a piece of healthy patellar tendon (0.2x0.5 cm) was excised from the remnants of the patellar tendon autograft during anterior cruciate ligament reconstruction. All specimens were cleaned in sterile saline, fixed in buffered formalin and then used to prepare 5-µm thick paraffin-embedded sections.

Immunohistochemical staining
Sections (5 µm thick) of representative blocks containing tendinosis or healthy patellar tendon tissues were mounted on 3-aminopropyl-triethoxy-silane (Sigma Chemical, St Louis, MO, USA) and dried overnight at 40°C. After removal of paraffin and dehydration, two consecutive paraffin sections from each sample were quenched with 0.5% hydrogen peroxide for 20 min and transferred to 10 mmol/l citrate buffer solution (pH 6) and boiled in a microwave oven for 1 min. After cooling, the sections were digested with 0.1% trypsin for 10 min, and incubated with 1% bovine serum albumin in phosphate-buffered saline (PBS) for 20 min. Primary antibody, either a mouse monoclonal anti-human PCNA antibody (Oncogene Products, Boston, MA, USA) or a goat monoclonal anti-human PDGFRß antibody (Santa Cruz, CA, USA), at a dilution of 1:100, was added to the sections, which were kept in a humid chamber at 4°C overnight. After four washes in PBS, the sections were incubated for 30 min with secondary antibody [a biotinylated anti-mouse IgG (Dako, Glostrup, Denmark) for PCNA and a biotinylated anti-goat IgG (Dako) for PDGFRß] at a dilution of 1:100. After three washes in PBS, the sections were incubated in avidin–biotin complex (Dako kit) for 60 min. The sections were then exposed for 4 min to a 1% solution of 3,3'-diaminobenzidine tetrahydrochloride for colour development. Finally, the sections were rinsed in distilled water, counterstained in Mayer's haematoxylin, dehydrated through graded alcohol to xylene, and mounted in Permount [16]. For better reproducibility and comparability, all incubation times were strictly controlled. Control slides were prepared by omitting the primary antibody (negative controls) and histological sections (positive controls) with known expression of PCNA and PDGFRß. Immunohistochemical staining for PDGFBB was also performed according to the same protocol, with a monoclonal anti-human PDGFBB primary antibody (R&D Systems, Minneapolis, MN, USA).

Semi-quantitative immunohistometry
Firstly, all slides were investigated to examine the quality of brown immunopositive staining for PCNA and PDGFRß; the pixel threshold values could be determined by visual inspection. To minimize assessment bias, a double-blind design was used. Measurements were performed at x400 magnification. Ten viewing fields (0.038 µm2 each) per slide were sampled systematically to avoid allocation bias. Fields of view including endothelial cells and synovium cells were skipped and replaced with adjacent fields. Semi-quantitative analysis of PCNA and PDGFRß immunostaining was performed with the Leica Q500MC Image Analysis System (Leica, Cambridge, UK).

For immunohistometric measurement, hue– saturation–intensity (HSI) colour coding was used for the measurement of mean colour saturation of immunopositive cells, which corresponds to the expression level of the measured antigen. HSI coding was chosen because it specifies colour by hue, excludes features that are too light or too dark by intensity, but allows measurement of the amount of the specified colour by saturation. The pixel threshold values (full range 0–255) of immunopositive brown colour were recorded as follows: hue, 128–142; saturation, 0–255; intensity, 22–128. Similarly, the pixel threshold values for brown and blue colour, representing the total number of cells, were recorded as follows: hue, 30–142; saturation, 0–255; intensity, 22–145.

A proliferative index, defined as the number of PCNA-immunopositive nuclei as a percentage of the total number of nuclei, was calculated as the average of 10 viewing fields for each section. Similarly, the percentage of PDGFRß-immunopositive cells per field of view and the corresponding immunopositivity were determined.

Explant cell culture
Tendon cells were prepared from samples taken from nine patients undergoing surgery for patellar tendinosis, and eight age- and gender-matched patients who underwent reconstruction of the anterior cruciate ligaments using the patellar tendon as a healthy autograft, adapted from the methods we have used to culture rat tendon fibroblasts [12]. Immediately after surgical removal, the fresh samples for primary explant culture were rinsed twice with sterilized PBS and once with 1% penicillin–streptomycin–neomycin antibiotic mixture in PBS. The fatty tissues and blood vessels attached to the explants were removed and placed in serum-free Dulbecco's Modified Eagle Medium (DMEM). After the explants had been cut into small pieces (1x1 mm) under sterile conditions, they were placed in trypsin/EDTA solution for 5 min. Ten per cent fetal bovine serum (FBS) in DMEM was used to neutralize the effect of trypsin. The small explants were placed in 35-mm culture dishes and cultured with 10% FBS/DMEM. After the fibroblasts had migrated from the explant tissue and reached confluence, the fibroblasts were trypsinized for 3 min at 37°C. Trypsin activity was neutralized with 1 ml of 10% FBS/DMEM. The trypsinized fibroblasts were centrifuged at 1500–1700 r.p.m. for 5 min, washed with plain medium and resuspended in fresh 10% FBS/DMEM. Cell density was determined and the cells were seeded into a 25 cm2 culture flask at a density of 2x105 cells per flask.

Proliferation of tendinosis cells and healthy tendon fibroblasts
Tendinosis cells and healthy tendon fibroblasts from the culture flask were trypsinized and washed with serum-free DMEM. The fibroblasts were seeded in 96-well microtitre plates at a density of 3000/well in triplicate. The proliferation rates of cell cultures supplemented with 10% FBS were measured on days 0, 3, 6, 9, 12 and 15. For the measurement of proliferative responses at various concentrations of FBS, seeded cells were exposed to serum-free DMEM for 24 h and then transferred to 0, 5, 10 or 20% FBS/DMEM. The proliferation rate was measured at day 6 of culture. To measure the proliferative response to PDGFBB, seeded cells at a density of 5000/well were starved of FBS for 24 h before being exposed to PDGFBB, and the proliferation rate was measured after 48 h of incubation with PDGFBB.

Cell proliferation assay
Cell proliferation rate was measured with a 5-bromo- 2'-deoxyuridine (BrdU) incorporation assay kit (Boehringer) [17].

Immunocytochemical staining of PDGFRß
Tendinosis and healthy tendon fibroblasts were trypsinized and seeded in four-well chamber slides (Nunc) at a density of 50 000/well. At confluence, the fibroblasts were fixed with 4% paraformaldehyde/phosphate buffer for 24 h at 4°C and quenched with 0.5% hydrogen peroxide for 20 min. The slides were then incubated with goat monoclonal anti-human PDGFRß primary antibody in a humid chamber at 4°C overnight. The procedures for application of second antibody, colour development and counterstaining were similar to the immunohistochemical procedures described above. Finally, the slides were dehydrated through graded alcohol solutions and mounted with glycerol before microscopic examination.

Statistics
Statistical analysis was performed by SPSS 9.0. As all data to be tested were found to be normally distributed by the Kolmogorov–Smirnov test, Student's t-test was used to compare the proliferative index, the percentage of PDGFRß-positive cells and immunopositivity of PDGFRß between tendinosis tissue and healthy patellar tendon tissue. Two-way analysis of variance and the Bonferroni test were employed to compare the proliferative responses of tendinosis cells and control tendon fibroblasts with respect to day of culture, level of FBS supplementation and PDGFBB supplementation. Significance was accepted at P<0.01, in order to compensate for inflated type I error due to multiple tests.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
All patellar tendinosis samples exhibited hypercellularity and disrupted collagen matrix to various extents, as revealed by haematoxylin/eosin staining, whereas no histological abnormalities were found in the healthy patellar tendon controls.

Immunohistochemistry
Hypercellularity was observed in all patellar tendinosis samples but in none of the controls. Immunohistochemical staining for PCNA, PDGFRß and PDGFBB in tendinosis tissue and controls is shown in Fig. 1Go. The results of immunohistometric measurements are shown in Table 1Go.



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  		FIG. 1. PCNA immunostaining of tendinosis patellar tendon (A) and healthy patellar tendon (B), PDGFRß immunostaining of tendinosis patellar tendon (C) and healthy patellar tendon (D), and PDGFBB immunostaining of tendinosis patellar tendon (E) and healthy patellar tendon (F). Tendinosis tissues exhibited increased PCNA and PDGFRß expression but no obvious difference in PDGFBB expression. Magnification x600.

 

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  		TABLE 1. Results of immunohistometry

 
The increase in cell number in tendinosis tissues was statistically significant (P<0.001). PCNA staining demonstrated a higher proliferative index (P<0.001) in tendinosis tissues, indicating that the hypercellularity is likely to be caused by increased proliferation. Increased expression of PDGFRß was also clearly shown in both the percentage of immunopositive cells (P<0.001) and the immunopositivity for PDGFRß (P<0.001) in tendinosis tissue. There were no differences in immunohistochemical staining of PDGFBB (Fig. 1EGo and FGo). The correlation of the proliferation index with the percentage of positive cells and the mean saturation of PDGFRß immunostain were also statistically significant (r=0.757 and 0.702 respectively, P<0.001), reflecting the association of increased proliferation with increased PDGFRß expression.

Cell culture and proliferation assay
Cultured tendinosis cells had a higher proliferation rate than healthy controls (P<0.01). The higher proliferation capacity of tendinosis cells was maintained at different concentrations of FBS (P<0.01). Immunocytochemical staining for PDGFRß showed that cultured tendinosis cells had a higher expression level of PDGFRß (Fig. 2Go), while in the presence of 10 ng/ml PDGF tendinosis cells showed a higher proliferation rate (P<0.01) than healthy control cells (Table 2Go). This indicates that the higher proliferative capacity of tendinosis cells resulted partly from the higher level of expression of PDGFRß.



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  		FIG. 2. PDGFRß immunostaining of cultured tendinosis cells (A) and tendon fibroblasts from healthy control tissue (B), showing higher expression of PDGFRß in tendinosis. Magnification x400.

 

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  		TABLE 2. Results of proliferation assay in cell culture

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The present study is the first of its kind to demonstrate objectively the hypercellularity associated with increased cell proliferation and increased expression of PDGFRß in human patellar tendinosis. The PCNA staining unambiguously indicates the presence of a large number of clustering proliferating cells. This indicates that tendinosis, at least during the period of sampling, which was more than 6 months after the onset of subjective symptoms, is an ongoing process, and further increase in cellularity can be expected.

The tendinosis cells had different shapes and sizes compared with the tenocytes observed in the healthy controls. However, they may have originated from tenocytes, as they also expressed procollagen type I (B. Chan et al., submitted for publication).

Tendinosis is regarded as a chronic condition [2, 4, 7]. Chronic injury is characterized by slow insidious onset, implying an antecedent subthreshold spectrum of structural damage leading to a crisis episode that is heralded by pain and/or signs of inflammation lasting months to years and distinguished by persistent symptoms without resolution [18]. As is clearly shown by this study, the cells are not in a silent end-stage of a degenerative disorder but are involved in a highly active process. This suggestion is supported by the increased proteoglycan deposition [2, 3, 8]. The term ‘degeneration’ describes a change in a tissue from a greater to a less functionally active form, causing cell atrophy and degenerative change [18]. Patellar tendinosis cells show opposite signs, i.e. increased cellular activity.

The expansion of the cell population in fibrous tissues requires the disintegration of the collagenous matrix to provide free space, as seen from the characteristic gross disturbances of the collagen. This raises the possibility that tendinosis is rooted partly in alterations in cellular activities. It is thus very likely that any expansion of cell number will be at the cost of the fibrous structure of the tendon. The collagen fibres were indeed disrupted and disorganized in all the samples in our study.

Hypercellularity occurs in the early healing phase of any tendon injury, when the proliferating tenocytes retain their fibroblastic appearance and inflammatory cells are abundant [12]. The hypercellularity, disturbance of the collagen matrix and increased proteoglycan content found in tendinosis is strongly suggestive of a halt in the early phase of tendon healing, except for the absence of the inflammatory response. However, we cannot rule out previous inflammation in the tissues in the present study, as the duration of symptoms before surgery was more than 6 months. Furthermore, the absence of inflammatory cells may not rule out other inflammatory mediators.

A weakness of this study is that the samples were collected at a single time-point, after more than 6 months of subjective severe symptoms that prevented the patients from taking part in sports and other physical activities. For obvious reasons, there are no studies assessing tendinosis tissues over time from early onset of symptoms. Generally, the onset of symptoms is described vaguely by patients with tendinosis. It is therefore unlikely that a partial rupture of the tendon preceded the condition in these patients, as this would probably have involved the sudden onset of pain during activity.

In conclusion, this study shows clearly that the hypercellularity observed in patellar tendinosis is caused by increased cell proliferation associated with increased expression of PDGFRß.


   Acknowledgments
 
This work was supported by Earmarked Grant CUHK4255/98M (University Grant Committee, Hong Kong).


   Notes
 
Correspondence to: C. G. Rolf. Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 24 February 2000; Accepted 18 September 2000


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