Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis

144

Objective. Using radiography to assess the efficacy of a disease-modifying osteoarthritis (OA) drug on joint structure is challenging. Subchondral bone marrow abnormalities determined by magnetic resonance imaging (MRI) and urinary excretion of C-terminal crosslinking telopeptide of type II collagen (CTX-II) have recently been shown to be predictors of radiographic progression in patients with knee OA, suggesting that these may represent valuable biomarkers with increased sensitivity compared with findings on radiography. The aims of this investigation were to analyze, in patients with knee OA, whether the values associated with these 2 OA biomarkers can change within 3 months, and to investigate the relationships between bone marrow abnormalities and CTX-II.Methods. Knee MRI scans were obtained in 377 patients with painful knee OA (76% women, mean age 63 years, mean disease duration 6.6 years) at both baseline and 3 months. The femoral and tibial condyles and the patella were divided into 8 sites for the scoring of bone marrow abnormalities. A bone marrow abnormality was defined as an area of increased signal on T2-weighted images of the subchondral bone. All scans were reviewed centrally and scored by a single trained radiologist using a validated 4-point scoring method. Fasting urine and serum samples were also collected from all patients at baseline, month 1, month 2, and month 3, in order to measure the levels of urinary CTX-II and serum CTX-I, a biochemical marker of bone resorption.Results. At baseline, 82% of patients had MRI evidence of bone marrow abnormalities. Bone marrow abnormality scores correlated significantly with CTX-II levels (P < 0.0001). Within 3 months, the bone marrow abnormality score decreased in 37 patients (9.8%), increased in 71 patients (18.8%), and did not change in the majority of patients (71.4%). Patients with baseline urinary CTX-II levels in the highest tertile had a relative risk of 2.4 (95% confidence interval 1.1-5.0) of worsening bone marrow abnormalities at 3 months compared with patients with levels in the lowest tertile, after adjustment for age, sex, and body mass index. In patients who showed a decrease in the bone marrow abnormality score at 3 months, urinary CTX-II levels decreased significantly (mean ؊75 ng/mmole creatinine), whereas levels increased (mean ؉23 ng/mmole creatinine) in patients showing an increase in the bone marrow abnormality score (P ‫؍‬ 0.01 between the 2 groups). No significant association between bone marrow abnormalities and serum CTX-I was observed.Conclusion. In patients with painful knee OA, bone marrow abnormalities on MRI can change within only 3 months in ϳ30% of patients. Reduction in the extent of bone marrow abnormalities is associated with a decrease in cartilage degradation.Osteoarthritis (OA) of the knee frequently affects the elderly population and is characterized by cartilage loss, osteophytes, and subchondral sclerosis and cysts (1). Radiography is currently the only method accepted by regulatory agencies for assessing progress...

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Bone marrow abnormalities on magnetic resonance imaging are associated with type II collagen degradation in knee osteoarthritis: A three‐month longitudinal study

Garnero¹,

Peterfy²,

Zaim³

et al. 2005

144

“…However, the association between mean BMI and JSL was not found in a recent review (26). Our results are in contrast with studies showing a positive association between increased urinary CTX-II levels and progression of knee (33) or hip (34) OA, but are consistent with a study by Mazzuca et al, who found no relationship between urinary CTX-II and JSL (35). Type II collagen constitutes the most abundant protein of intervertebral discs.…”

Section: Knee Joint Space Study In Womensupporting

confidence: 79%

Radiologic assessment of age‐related knee joint space changes in women: A 4‐year longitudinal study

Gensburger

Arlot

Sornay‐Rendu

et al. 2009

Objective. To analyze a population-based cohort of women in order to establish normal values of joint space width (JSW) and to evaluate the existence of age-related joint space loss (JSL). Methods. Knee radiographs were performed 4 years apart in women from the OFELY (Os des Femmes de Lyon) Cohort. Posteroanterior radiographs of both knees were taken in semiflexion with a standardized fluoroscopically assisted protocol. Radiographs were qualitatively evaluated using a scoring system based on the Altman score that assessed joint space narrowing, osteophytes, and sclerosis for each tibiofemoral compartment and each side. For quantitative assessment, radiographs were digitized using a video camera, and specific software was used to measure JSW in every compartment. Results. We evaluated the radiographs of 606 women (ages 39 -90 years, mean 62 years) and found that in all subjects, JSW significantly decreased with age in every compartment (r ‫؍‬ ؊0.12 to ؊0.16, P < 0.001), including in 358 subjects without any radiographic abnormality related to osteoarthritis (OA) at baseline. The longitudinal analysis confirmed a significant loss over 4 years of ϳ0.30 mm (6%) for the medial compartment. Multiple regression analysis did not identify significant predictors of JSL among clinical risk factors and biochemical markers of bone and cartilage turnover. Conclusion. In this first longitudinal study of a population-based cohort of women, we have established normal values of JSW and shown that JSW decreases with aging, especially at the medial compartment, even in subjects without any radiographic abnormalities related to OA.

“…In this issue of Arthritis & Rheumatism, Garnero et al confirm and extend these observations (23). They also show that the amino propeptide of an apparently minor splice variant of type II procollagen, type IIA collagen, is detectable in serum even in healthy adults.…”

Section: Can Serum Biomarker Assays Measure the Progression Of Cartilmentioning

confidence: 71%

Can serum biomarker assays measure the progression of cartilage degeneration in osteoarthritis?

Poole

2002

A loss of homeostasis in the maintenance of a healthy articular cartilage leads to the pathologic degeneration of articular cartilage in osteoarthritis (OA). The preservation of a functional articular cartilage enables the survival of a tissue that covers articulating surfaces in a diarthrodial joint. With synovial fluid, articular cartilage provides an almost frictionless articulation enabling painless joint movement. The extracellular matrix of articular cartilage provides this tissue with its great strength, resistance to deformation, and ability to dissipate load and handle the forces generated within the joint. The collagen fibrillar network provides tensile strength, and the water-laden proteoglycan aggrecan, organized in a supramolecular aggregate, contributes its compressive stiffness. Ordinarily, articular cartilage can easily manage the high pressures, strains, and shear forces generated during running, jumping, stair climbing, and descent (1).In short, articular cartilage is a remarkable tissue and an engineering marvel. Yet this tissue is incapable of effective repair once growth ceases, mainly because of its lack of vascularity and the resulting inability to recruit chondroprogenitor (stem) cells. Its physical properties peak at an age of ϳ30 years and are usually progressively lost thereafter, much less in the ankle than in the hip or knee, but lost nonetheless. As we age, the degenerative process becomes more apparent. In a majority of the population over age 60, this process can result in OA (2). Clearly, our joints were never designed for us to live so long. Long life brings out the weaknesses in the maintenance of our structural design.This degeneration is not simply wear and tear, although the mechanical issues are extremely important. In the mouse bearing the active human collagenase 3 (matrix metalloproteinase 13 [MMP-13]) transgene, cleavage of type II collagen occurs throughout the articular cartilage, but it is only at sites of direct contact of articular cartilage that focal lesions develop (3). It is the combination of molecular damage and inability to effectively manage physical forces that leads to pathology. The latter must also involve altered loading on chondrocytes due to differences and alterations in joint shape and function and matrix degradation, resulting in joint incongruity and attendant macro-and microenvironmental changes in loading, promoting changes in matrix turnover and a loss of homeostasis. The net result is lesion development that we see so often at autopsy. In idiopathic OA, this process is likely to start and progress over the course of Ն20 years before clinical signs and symptoms are recognized.In more intact healthy aging articular cartilages, such as those in the ankle, these overt degradative changes are seen much less often. Here, there are no clear signs of progressive change in the distribution and amount of denatured type II collagen in relationship to the amount of collagenase-cleaved collagen, signs which are indicative of altered proteolysis of this co...