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Rheumatology 2001; 40: 140-146
© 2001 British Society for Rheumatology

Increased urinary pyridinoline cross-link compounds of collagen in patients with systemic sclerosis and Raynaud's phenomenon

R. Istok, L. Czirják1, J. Lukác, M. Stancíková and J. Rovensky

Research Institute of Rheumatic Diseases, Piest'any, Slovak Republic and
1 Nephrological Center and Second Department of Internal Medicine, Clinical Immunology Unit, University of Pécs, Medical Faculty, Pécs, Hungary


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To study concentration changes in collagen degradation markers in patients with diffuse and limited cutaneous systemic sclerosis and patients with scleroderma-related diseases.

Methods. Pyridinoline cross-link compounds were analysed in urine samples using high-performance liquid chromatography. Samples were analysed for pyridinoline (Pyr), deoxypyridinoline (Dpyr) and soft-tissue pyridinoline (stPyr) in patients with diffuse cutaneous systemic sclerosis (dcSSc, n=23) and limited cutaneous systemic sclerosis (lcSSc, n=48) and in patients with scleroderma-related diseases such as primary Raynaud's phenomenon (pRP, n=16) and secondary Raynaud's phenomenon (sRP, n=14). Healthy controls (n=18) and patients with post-menopausal osteoporosis (OP, n=35) were also investigated.

Results. Urinary Pyr, Dpyr and stPyr concentrations were significantly higher in patients with Raynaud's phenomenon and systemic sclerosis than in healthy controls. The highest concentrations (two to three times greater than in healthy controls) were found in patients with dcSSc. The stPyr concentration was significantly higher in patients with dcSSc than in those with lcSSc, sRP and pRP. No significant difference in stPyr concentration was found between the healthy controls and the OP group, suggesting that stPyr is derived from soft tissues rather than bone. The extent and severity of skin involvement, measured as a skin score, significantly correlated with the concentrations of stPyr and Pyr, whereas no such correlation was found for Dpyr.

Conclusions. Increased urinary concentrations of piridinoline cross-links reflect alterations in collagen turnover in both Raynaud's phenomenon and systemic sclerosis. The close correlation between stPyr concentration and the extent of skin involvement in systemic sclerosis suggests that this parameter may be useful in monitoring ongoing fibrosis in this disease.

KEY WORDS: Scleroderma, Systemic sclerosis, Raynaud's phenomenon, Fibrosis, Pyridinoline, Deoxypyridinoline.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Systemic sclerosis (SSc) is a disease of unknown causation that is characterized by vascular injuries, autoimmune phenomena, degenerative changes and fibrosis. The persistent overproduction of collagen and other extracellular matrix components results in excessive matrix deposition, and is responsible for the ongoing fibrosis in SSc [1]. Excessive collagen deposition results from an imbalance between the amount of newly synthesized collagen incorporated into the extracellular matrix and the quantity of both newly synthesized and mature collagen degraded.

Although most studies have focused on collagen synthesis (having investigated type III procollagen [2–4]), there has been growing interest in the collagen degradation processes associated with fibrosis. The most common approach involves the investigation of collagen-degrading enzymes, mainly the study of collagenase in vitro [5–7]. However, the results are difficult to interpret in terms of the in vivo situation, as a combination of several enzymes, including the corresponding inhibitors, probably participates in the degradation of a single collagen fibre. A different approach is to study the degradation products as they appear in vivo. In this respect, urinary collagen cross-links pyridinoline (Pyr) and deoxypyridinoline (Dpyr) and serum levels of the cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) have been studied [8–10]. Recently, Hunzelmann et al. [10] have found a close correlation between serum ICTP levels and the extent of skin fibrosis in patients with SSc.

Pyr, a trifunctional 3-hydroxypyridinium cross-link compound, and its minor analogue Dpyr are two non-reducible collagen cross-links [11]. Pyr is found in collagen types I, II, III, V, XI and is believed to be important in maintaining the structure of the collagen fibril network in the matrix of various tissues. In scleroderma, accumulation of collagen types I, III, IV and VI was found in the skin and the perivascular regions [1]. Pyr is distributed in most collagenous tissues, cartilage, ligaments, tendon and bone, while significant amounts of Dpyr are more specifically distributed in bone collagen type I [12]. Both Pyr and Dpyr originate from mature collagen; they are not metabolized but are excreted free or peptide-bound in the urine. In most circumstances, bone collagen degradation is the major contributor to both cross-link compounds in the urine, and consequently the urinary levels of both compounds are used mainly as markers of bone resorption [13].

La Montagna et al. [8] reported a significant increase in Pyr in the urine of patients with SSc. From the correlation they found between Pyr and bone density, the authors considered this result to be a consequence of accelerated bone resorption in SSc. However, Stone et al. [9] suggested that, in spite of Dpyr, which originates almost exclusively from bone, the increased Pyr concentration in SSc patients could also originate from the soft tissues. As the Pyr:Dpyr ratio in bone is 3.5:1, the authors estimated the levels of urinary Pyr derived from soft tissue (stPyr) collagen degradation using the equation [stPyr]=[Pyr]-3.5x[Dpyr]. They found significantly elevated levels of urinary stPyr in patients with SSc in comparison with controls. It was suggested that determination of Pyr and Dpyr in the urine could provide insight into mature collagen degradation in both skeletal and soft tissues in vivo.

The aim of our study was to extend our knowledge about urinary pyridinoline cross-link compounds, especially Pyr derived from soft tissues in patients with diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). We were also interested in the correlation between stPyr and the extent of skin involvement. Patients with primary (pRP) and secondary Raynaud's phenomenon (sRP) were also investigated. The levels of stPyr have not yet been investigated in pRP and sRP. To verify the specificity of stPyr for Pyr originating from soft tissue, we also measured this parameter in a group of patients with osteoporosis (OP).


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients
This report is based on an analysis of the clinical and laboratory findings of patients with SSc and scleroderma-related disorders treated at the Nephrological Center and the Second Department of Internal Medicine at the University of Pécs, Hungary, and the Research Institute of Rheumatic Diseases, Piest'any, Slovak Republic, between 1995 and 1999. Both departments used the same standard protocol for the clinical investigation [14, 15]. All the patients with scleroderma met the diagnostic criteria for SSc [16]. The basic demographic data and clinical features of the patients at the time of urine sampling are shown in Table 1Go. Patients with SSc were divided into subgroups having dcSSc and lcSSc according to LeRoy et al. [17]. The skin scores of patients were evaluated by the method of Kahaleh et al. [18]. The patients had not received any therapy which might affect collagen turnover or the underlying disease process (e.g. steroids, D-penicillamine) for at least 1 month before the urine sample was taken. General exclusion criteria included signs of serious renal impairment and clinically overt osteoporosis, or bone fractures within 1 yr before the study.


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  		TABLE 1. Clinical data of patients with SSc

 
The criteria of LeRoy and Medsger [19] were used for patients with pure primary Raynaud's phenomenon (n=16). Patients with the following characteristics were included in this category: episodic attacks of acral pallor or cyanosis, strong symmetrical peripheral pulses, no evidence of digital pitting scars, ulcerations or gangrene, normal nail-fold capillaries [19, 20], a negative antinuclear antibody test and a normal erythrocyte sedimentation rate. Patients with pRP did not show any clinical or laboratory signs of the presence of systemic autoimmune disease. A barium meal test, chest X-ray and Schirmer's test (lachrymal secretion rate) were carried out in all cases. Patients showing a significant cervical compression syndrome (thoracic outlet or other syndromes) or carpal tunnel syndrome were also excluded. Patients with vibration-induced white fingers or drug-induced Raynaud's phenomenon were also excluded.

sRP may be caused by several underlying diseases, including systemic autoimmune disorders [20]. A special group of patients with Raynaud's phenomenon was selected for this study; they exhibited the clinical signs of Raynaud's phenomenon as their only predominant clinical symptom. These patients also had antinuclear antibody positivity and/or a scleroderma capillary pattern or digital pitting ulcerations/gangrene, but did not have any internal organ manifestation (e.g. pulmonary interstitial changes, oesophageal dysmotility, colon abnormalities, renal symptoms etc). We describe this special group of 14 patients as having secondary Raynaud's phenomenon. Both groups of patients with Raynaud's phenomenon were treated with pentoxifyllin and calcium channel blockers.

Thirty-five female out-patients (mean age±S.D. 59.1±12.6 yr) with densitometrically (Hologic QDR®-4500, Waldham, MA, USA) proved post-menopausal OP and 18 healthy controls (16 females, two males; mean age 52.3±6.8 yr) were also investigated as controls.

Methods
Urine samples were collected as second-void fasting urine between 8 and 10 a.m. and stored at -20°C until assayed for collagen cross-links. Urinary Pyr and Dpyr were determined by high-performance liquid chromatography with fluorescence detection [21]. Briefly, Pyr and Dpyr were isolated from urine hydrolysates by standard cellulose partition chromatography and separated isocratically using a cation exchange column. Fluorescence detection was performed at excitation and emission wavelengths of 295 and 400 nm respectively. The Pyr standard was kindly supplied by Professor S. P. Robins (Rowett Research Institute, Aberdeen, UK).

The chromatographic system consisted of an LC 10 AD pump, a CR 6A integrator, an RF 551 spectrofluorimetric detector (Shimadzu, Kyoto, Japan), an R 7725 sample injector (Rheodyne, USA) and a HEMA BIO 1000 SB column (250x4 mm) (Tessek, Prague, Czech Republic). The mobile phase was prepared by mixing 0.45 M sodium sulphate and 0.3 M acetate buffer, pH 3.0 (9:22). Analysis was performed at a flow rate of 0.8 ml/min. The results were expressed as nanomoles of Pyr, Dpyr or stPyr per millimole of creatinine; urinary creatinine was determined using the spectrophotometric method using an automatic clinical analyser (Roche Diagnostics/Hitachi 911 Systems).

Statistical analysis
The results were analysed with the unpaired Mann–Whitney test. Correlations between collagen cross-links and skin score were calculated using Pearson's correlation coefficient.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
The urinary concentrations of Pyr were significantly increased in all patient groups (dcSSc, lcSSc, sRP, pRP and OP) compared with healthy controls (Fig. 1Go). The highest median was measured in patients with dcSSc (about twice as high as in OP and about three times higher than in the healthy control group). Urinary Pyr concentrations also showed a significant difference between dcSSc and the pRP and sRP groups (P<0.05).



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  		FIG. 1. Comparison of pyridinoline concentrations in different groups of patients. The figure shows concentrations for each individual patient in the following groups: HC, n=18; OP, n=35; pRP, n=16; sRP, n=14; lcSSc, n=48; dcSSc, n=23. The horizontal and vertical lines represent medians and interquartile ranges respectively. Significances of differences among groups: healthy control vs dcSSc P<0.00001, vs lcSSc P<0.00001, vs sRP P<0.001, vs pRP P<0.00001, vs OP P<0.00001; OP vs dcSSc P<0.001, vs lcSSc P<0.001, vs sRP and pRP not significant.

 
All patient groups, including the pRP and sRP groups, also had significantly higher Dpyr concentrations than the healthy control group, but only dcSSc patients had higher concentrations than OP patients (Fig. 2Go).



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  		FIG. 2. Comparison of deoxypyridinoline concentrations in different groups of patients. See caption of Fig. 1Go for numbers of patients in each group. Significances of differences among groups: healthy control vs dcSSc P<0.00001, vs lcSSc P<0.00001, vs sRP P<0.001, vs pRP P<0.00001, vs OP P<0.00001; OP vs dcSSc P<0.05, vs lcSSc, sRP and pRP not significant.

 
There was no significant difference in the levels of stPyr between the healthy control and OP groups, which suggests that stPyr does not originate from bone collagen. Markedly increased concentrations were found in the dcSSc, lcSSc, sRP and pRP groups; the medians for stPyr were 4.0, 2.5, 1.9 and 1.7 times higher respectively than those in the controls (Fig. 3Go). There was also a significant difference between the stPyr concentrations in patients with dcSSc compared with the lcSSc, pRP and sRP groups (P<0.05).



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  		FIG. 3. Comparison of soft-tissue pyridinoline concentrations in different groups of patients. See caption of Fig. 1Go for numbers of patients in each group. Significances of differences among groups: healthy control vs dcSSc P<0.00001, vs lcSSc P<0.001, vs sRP P<0.001, vs pRP P<0.05, vs OP not significant; OP vs dcSSc P<0.001, vs lcSSc P<0.001, vs sRP and pRP not significant.

 
The extent and the severity of skin involvement (measured by the skin score) correlated significantly with the concentrations of Pyr (r=0.46, P<0.0001) and stPyr (r=0.62, P<0.0001) (Fig. 4Go) but not with those of Dpyr (r=0.22, P=0.07). No correlation was found between Pyr, stPyr levels and pulmonary or oesophageal involvement in patients with SSc.



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  		FIG. 4. Regression plot of stPyr levels vs skin score in all patients with SSc (lcSSc+dcSSc). Pearson's correlation coefficient: r=0.62, P<0.0001.

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
The dermis contains eight types of collagen. Type I collagen is the most abundant protein, constituting about 80–85% of skin collagen, whereas type III collagen is responsible for about 10–15% and the minor collagens for around 5%. Although it is known that both type I and type III collagen are able to form Pyr cross-links, a very small amount of Pyr was found in healthy skin and no Dpyr could be detected at all, unlike findings in bone [12]. The accumulation of collagen types I and III in scleroderma skin is well known [22, 23], and the total number of cross-links can increase without any significant qualitative changes in the cross-linking process. Furthermore, the expression of lysyloxidase, the enzyme that participates directly in the formation of collagen cross-links, is elevated in scleroderma skin [24]. Recent studies have also shown an increased content of Pyr and Dpyr and an elevated ratio of Pyr:Dpyr in lipodermatosclerosis (a localized fibrotic disease associated with varicose vein syndrome) [25]. Moriguchi and Fujimoto [26] demonstrated marked accumulation of Pyr cross-links in the skin during the formation of hypertrophic scars. Our analysis of the fibrotic tissues of an SSc autopsy patient (skin, fascia, endocardium and urinary bladder) also showed that a significant amount of Pyr is present in the fibrotic skin, as well as in the other fibrotic tissues analysed, which can contribute to the Pyr found in the urine [27]. The significant increase in histidinohydroxylysinonorleucine, another type of collagen cross-link characteristic of skin collagen, was also found in the skin of systemic sclerosis patients [28].

One aim of our study was to show whether the definition of stPyr actually reflects Pyr derived from soft tissues rather than from bone, as suggested by Stone et al. [9]. The absence of a significant difference in stPyr concentrations between the healthy control and OP groups clearly suggests that this parameter mainly reflects Pyr released from soft tissues. Nevertheless, approximately 20% of OP patients had stPyr concentrations above the normal range. This observation could be explained partly by the excretion of Pyr from cartilage due to subclinical osteoarthrosis, which is common in the elderly. Another fact pointing to stPyr as a marker for soft tissue degradation is the strong association between stPyr and the extent and severity of skin involvement (measured by skin score) in patients with SSc (r=0.62, P<0.0001). This correlation is very similar to that found by Hunzelmann et al. [10] between the serum level of ICTP and the skin score of SSc patients (r=0.64, P<0.01). The levels of Pyr themselves also correlate with the skin score; however, this correlation is not as close as that with stPyr. Furthermore, no significant correlation was found between Dpyr and skin score.

Like Stone et al. [9], we detected increased Dpyr levels in patients with SSc. This finding could be explained by the incidence of increased bone turnover in some post-menopausal women (subclinical osteoporosis). Nevertheless, the possibility that increased synthesis of collagen in sites of fibrosis causes not only Pyr but also Dpyr cross-links to accumulate cannot be ruled out. Dpyr is excreted into the urine during increased degradation in a similar fashion to Pyr. However, the greater Pyr excretion and significantly higher levels of stPyr in patients with SSc in comparison with both healthy controls and patients with OP suggest that it is particularly Pyr which probably accumulates at sites of ongoing fibrosis. This hypothesis is also supported by the fact that stPyr levels were significantly higher in our patients with dcSSc than in the lcSSc patients (Fig. 3Go). Patients with lcSSc exhibit skin involvement that is limited to the hands, face and feet. Conversely, cases with dcSSc have both trunk and acral skin involvement, and their skin score is often high [17].

No significant association could be established between stPyr and the presence of pulmonary and oesophageal involvement in our SSc patients. However, the number of patients with severe pulmonary fibrosis was low in our groups (<20%). Stone et al. [9] found significantly higher concentrations of stPyr in SSc patients in comparison with other pulmonary disorders, such as chronic obstructive pulmonary disease and cystic fibrosis, which also suggests that the lung is not the primary site of stPyr production. The lung contains less collagen than the skin, and probably does not contribute significantly to Pyr production and excretion in urine. Our findings are also in accordance with the observation of Hunzelmann et al. [10], who investigated the association between circulating ICTP and the involvement of different organs (oesophagus, lung, heart) in patients with SSc, and could not find any correlation.

Pyr, Dpyr and stPyr levels were also found to be elevated in patients with pRP and sRP, although these increases were less significant than that found in the SSc groups. Despite the increased stPyr concentrations, the Pyr:Dpyr ratio was similar to that calculated for the controls (mean values of Pyr/Dpyr:pRP=6.0; sRP 6.7, healthy controls, 6.7), suggesting that increased stPyr levels could have resulted from an increased rate of collagen metabolism that probably affected all three parameters (Pyr, Dpyr and stPyr) in a similar manner. At least some of the patients in the sRP group may be regarded as potential candidates for later development of a scleroderma-related disease. However, similar changes were also observed in the pure pRP group. These latter patients will most probably never develop any scleroderma-related disorder with collagen accumulation. It is tempting, therefore, to speculate that the altered collagen metabolism may be predominantly explained by the ischaemic–reperfusion injury known to be associated with Raynaud's phenomenon [29].

In conclusion, this study demonstrates significantly increased urinary excretion of the stable collagen cross-links Pyr and Dpyr both in patients with Raynaud's phenomenon and in those with systemic sclerosis. However, the concentration of stPyr, which reflects pyridinoline cross-links originating in soft tissues, is higher in patients with SSc compared than in those with Raynaud's phenomenon. The strong correlation found between stPyr and the extent of fibrotic skin involvement in SSc patients may offer a new biochemical approach to the detection of ongoing fibrosis in scleroderma.


   Notes
 
Correspondence to: R. Istok, Research Institute of Rheumatic Diseases, Nabr. I. Krasku 4, 921 01 Piest’any, Slovak Republic Back


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 8 March 2000; Accepted 2 September 2000


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