Role of cartilage oligomeric matrix protein (COMP) as a prognostic biomarker in follow-up of early rheumatoid arthritis patients: Correlation to musculoskeletal ultrasonographic findings

Aim of the work

To assess the level of serum cartilage oligomeric matrix protein (COMP) in early rheumatoid arthritis (RA) patients and study its relation to disease activity and musculoskeletal ultrasound (MSUS) findings.

联合检测尿C-末端Ⅱ型胶原 血清软骨寡聚基质蛋白和硫酸软骨素846在骨关节炎早期诊断中的价值

目的评价联合检测尿C-末端Ⅱ型胶原(CTX-Ⅱ)、血清软骨寡聚基质蛋白(COMP)和硫酸软骨素846(CS-846)等生物学标志物在骨关节炎早期诊断中的价值。方法采用VAS评分法对患者疼痛程度进行评估后摄X线片,采用ELISA法检测骨关节炎患者及健康对照组血清中COMP、CS-846的浓度及尿液中CTX-Ⅱ浓度,并对上述指标进行相关性分析。结果骨关节炎组尿CTX-Ⅱ、血清COMP和CS-846含量均高于对照组,随着骨关节炎患者VAS评分及关节间隙狭窄程度的升高或加重,尿C-末端Ⅱ型胶原、血清COMP和CS-846水平逐渐升高。统计学分析结果显示,尚不能认为血清COMP水平与疼痛VAS评分之间有相关性,但其与关节间隙狭窄程度之间存在相关性;而血清CS-846水平及尿CTX-Ⅱ与疼痛VAS评分及关节间隙狭窄程度之间均有相关性。结论联合检测尿CTX-Ⅱ、血清COMP和CS-846等生物学标志物有望成为骨关节炎早期诊断的一种有效方法,但临床应用尚需要有更确切的循证医学证据。     

Diagnostic and prognostic value of some biochemical markers in early knee osteoarthritis

BackgroundOsteoarthritis (OA); the most common joint disease, is not only characterized by cartilage destruction; but also by alteration of bone and synovial tissue metabolism, though their relative importance in the initiation and progression of OA is still debated. To identify patients with a high risk for destructive OA, more sensitive techniques than plain X-rays are needed.Aim of the workTo study the diagnostic and prognostic value of some biochemical markers serum hyaluronic acid (HA) and serum cartilage oligomeric matrix protein (COMP), high sensitive C-reactive protein (hs-CRP) in the included patients had early OA knees and their relation to disease progression.Patients and methodsSixty patients had early knee OA and 20 control subjects were included. WOMAC index, laboratory investigations (COMP, HA, hs-CRP) and radiological evaluation (Kellgren and Lawrence grading scale and Thomas compartmental score) were performed for each patient at baseline and after one year.ResultsHA was significantly higher in patients than controls (p > 0.001) with the highest specificity and positive predictive value. It was significantly correlated with COMP at baseline and after one year (p = 0.01). The levels of HA at baseline correlated with its levels after one year (p > 0.001). It also correlated with K–L grading score (p = 0.02). COMP was significantly higher in patients than controls (p > 0.001). It was significantly correlated with Thomas score after one year (p = 0.007). Baseline levels of COMP correlated significantly with its levels after one year (p = 0.005). The differences of the serum levels of hs-CRP at the baseline evaluation and after one year between patients and controls were not statistically significant (p = 0.4, 0.5, respectively).ConclusionsThe measurements of HA and COMP may be of diagnostic and prognostic value in differentiating patients with early joint destruction and in determining disease progression. A single biochemical marker has definitive diagnostic value and the combination with other biochemical markers as well as with clinical and radiographic data would most likely help to improve the clinical assessment of patients. Serum hs-CRP is not a good predictor of individual patient progression and has a poor sensitivity and specificity.     

Comparison of long‐term outcomes of drug‐eluting stents and bare metal stents for saphenous vein graft stenosis

Objective : Our aim was to compare the long‐term outcomes between drug‐eluting stents and bare‐metal stents for saphenous vein graft stenosis. Background : The ideal type of stent to treat saphenous vein graft stenosis has not been clearly established. Short‐term randomized controlled trial results comparing drug‐eluting stents with bare‐metal stents for saphenous vein graft stenosis are conflicting, intermediate‐term retrospective studies and meta‐analyses at two years suggest no difference in outcomes, and there are no long term follow‐up studies. The need for long term follow‐up data has become emerged with concern over late stent thrombosis. Methods : 246 saphenous vein graft patients undergoing stenting from August 2002–December 2008 were studied. Overall survival and event‐free survival were compared by Kaplan‐Meier method. Hazard ratios (HR) were calculated by Cox‐proportional hazards models. Results : We treated 133 patients with DES (median follow‐up four years) and 113 patients with BMS (median follow‐up four years) for SVG stenosis. Overall survival (77.0% ± 3.9% vs. 70.6% ± 4.6%, log‐rank P = 0.60) and MACE‐free survival (57.5% ± 4.6% vs. 56.8% ± 4.9, log‐rank P = 0.70) were not significantly different between the DES and BMS groups. Although BMS was associated with increased risk of target lesion revascularization (TLR) (freedom from TLR 85.2% ± 3.5% vs. 90.0% ± 3.0%, HR 2.07, 95% CI 0.97–4.42, log‐rank P = 0.05), there was no significant difference in the freedom from myocardial infarction (86.7% ± 3.3% vs. 88.7% ± 3.2%, log‐rank P = 0.39) or target vessel revascularization (77.1% ± 4.2% vs. 76.1% ± 4.2%, log‐rank P = 0.33) between the two groups. Conclusions : Although mortality is not statistically different between DES and BMS for SVG stenosis, BMS is associated with increased risk of revascularization, thus suggesting the superiority of DES over BMS in the long term. © 2011 Wiley Periodicals, Inc.     

Altered Synthesis of Cartilage-Specific Proteoglycans by Mutant Human Cartilage Oligomeric Matrix Protein

Background

The mechanism by which mutant cartilage oligomeric matrix protein (COMP) induces a pseudoachondroplasia phenotype remains unknown, and the reason why a mutation of a minor protein of the growth plate cartilage causes total disruption of endochondral bone formation has not yet been determined. The current study was performed to investigate the effects of mutated COMP on the synthesis of the cartilage-specific major matrix proteins of Swarm rat chondrosarcoma chondrocytes.

Methods

The Swarm rat chondrosarcoma chondrocytes transfected with a chimeric construct, which consisted of a mutant gene of human COMP and an amino acid FLAG tag sequence, were cultured in agarose gel. Formation of extracellular proteoglycan and type-II collagen by the cells was evaluated by immunohistochemical staining and measuring the ³⁵S-sulfate incorporation.

Results

No difference was observed for the detection of type-II collagen among the cell lines expressing mutant COMP and the control cell lines. Histochemical staining of sulfated proteoglycans with safranin-O showed that lesser amounts of proteoglycans were incorporated into the extracellular matrix of the chondrocytes transfected with the mutant gene. ³⁵S-sulfate incorporation into the cell/matrix fractions demonstrated markedly lower radiolabel incorporation, as compared to that of the control cells.

Conclusions

Mutation of COMP has an important impact on the processing of proteoglycans, rather than type-II collagen, in the three-dimensional culture of Swarm rat chondrosarcoma chondrocytes.     

Homozygosity for a missense variant in COMP gene associated with severe pseudoachondroplasia

The phenotypic spectrum associated with heterozygous mutations in cartilage oligomeric matrix protein gene (COMP) range from a mild form of multiple epiphyseal dysplasia (MED) to pseudoachondroplasia (PSACH). However, the phenotypic effect from biallelic COMP variants is unclear. We investigated a large consanguineous Pakistani family with a severe form of PSACH in 2 individuals. Another 14 family members presented with a mild PSACH phenotype similar to MED. Using exome sequencing and subsequent segregation analysis, we identified homozygosity for a COMP missense variant [c.1423G>A; p.(D475N)] in the 2 severely affected individuals, whereas family members with the mild PSACH phenotype were heterozygous. Our observations show for the first time that a biallelic COMP variant may be associated with pronounced and widespread skeletal malformations suggesting an additive effect of the 2 mutated alleles.     

体外冲击波联合康复治疗对早中期膝骨关节炎病人Coll2-1、COMP水平的影响

目的 探讨体外冲击波联合康复治疗对早中期膝骨关节炎（knee osteoarthritis, KOA）病人的治疗效果及其对关节液中胶原蛋白2-1（Collagen2-1, Coll2-1）、软骨寡聚基质蛋白（COMP）水平的影响。方法 选取2014年6月至2016年12月间收治的72例膝骨关节炎病人,随机分为对照组（36例）和观察组（36例）,对照组病人给予关节腔内注射玻璃酸钠治疗,观察组给予体外冲击波治疗,且两组均给予康复理疗措施。分别在治疗前及治疗后2个月时,采用活动时疼痛视觉模拟量表（visual analogue scale, VAS）评分、骨关节炎病人疼痛指数（Lequesne index）和美国西部安大略和麦克马斯特大学（the Western Ontario and McMaster Universities, WOMAC）骨关节炎指数评价两组的疗效,采用酶联免疫吸附试验（ELISA）测定关节液中Coll2-1、COMP的含量。结果 两组病人治疗后的VAS评分、Lequesne指数、WOMAC评分均明显降低（P均＜0.05）,治疗后观察组各项评分明显低于对照组（P均＜0.05）。治疗后两组病人关节液中Coll2-1、COMP的水平均比治疗前显著下降（P均＜0.05）,观察组下降程度明显优于对照组（P均＜0.05）。结论 体外冲击波联合康复治疗对膝骨关节炎病人的疗效较好,可明显减轻关节疼痛,改善膝关节活动功能,且明显降低病人关节液中的Coll2-1、COMP水平。     

Identification of cartilage oligomeric matrix protein (COMP) gene mutations in patients with pseudoachondroplasia and multiple epiphyseal dysplasia

Mutations in the cartilage oligomeric matrix protein (COMP) gene are responsible for two dominantly inherited skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). Mutation analysis of the COMP gene in Korean patients with PSACH and MED was performed. All nine patients with PSACH had mutations in the COMP gene, while three of the five patients with MED had detectable COMP mutations. Eight mutations, including three novel mutations, were identified in the COMP gene in the patients with PSACH and MED. Six mutations were found within the calmodulin-like repeats (CLRs) domain, especially in the seventh CLR and the other two mutations were in exon 16 outside of CLRs, which encode the C-terminal globular domain. Among the three novel mutations, two were missense mutations (Asp473Tyr, Asp482His) and one was a consecutive two-codon deletion, delAspAsp(469–473) in the five consecutive aspartic acid residues. All three novel mutations produced the PSACH phenotype. Electronic Publication