scholarly journals A low cartilage formation and repair endotype predicts radiographic progression of symptomatic knee osteoarthritis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yunyun Luo ◽  
Jonathan Samuels ◽  
Svetlana Krasnokutsky ◽  
Inger Byrjalsen ◽  
Virginia B. Kraus ◽  
...  
Keyword(s):  
Cartilage Repair ◽  
Radiographic Progression ◽  
Type Ii Collagen ◽  
Joint Space ◽  
Phase Iii ◽  
Type Ii ◽  
Collagen Formation ◽  
Cartilage Formation ◽  
Symptomatic Knee Osteoarthritis ◽  
Symptomatic Knee

Abstract Background Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation. Materials and methods The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width. Results In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4–8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011). Conclusion Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug. Level of evidence Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.

scholarly journals A low cartilage formation and repair endotype predicts radiographic progression of symptomatic knee osteoarthritis

2020 ◽  
Author(s):  
Yunyun Luo ◽  
Jonathan Samuels ◽  
Svetlana Krasnokutsky ◽  
Inger Byrjalsen ◽  
Virginia B. Kraus ◽  
...  
Keyword(s):  
Cartilage Repair ◽  
Radiographic Progression ◽  
Type Ii Collagen ◽  
Joint Space ◽  
Phase Iii ◽  
Type Ii ◽  
Collagen Formation ◽  
Cartilage Formation ◽  
Symptomatic Knee Osteoarthritis ◽  
Symptomatic Knee

Abstract Objective: Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study was to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation. Methods: The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n=106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n=147). The risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Progression was defined as two-year JSN > 0.35 mm. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width.Results: In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared to subjects with high PRO-C2. The mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 [1.4 – 8.6]-fold higher risk of progression. There was no significant effect of sCT treatment, compared to placebo, on JSN over two years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared to the moderate/high group (chi-squared = 6.5, p = 0.011). Conclusions: Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug.

scholarly journals A Novel High Sensitivity Type II Collagen Blood-Based Biomarker, PRO-C2, for Assessment of Cartilage Formation

2018 ◽  
Vol 19 (11) ◽  
pp. 3485 ◽  
Author(s):  
Yunyun Luo ◽  
Yi He ◽  
Ditte Reker ◽  
Natasja Gudmann ◽  
Kim Henriksen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Growth Factor ◽  
Knee Osteoarthritis ◽  
High Sensitivity ◽  
Type Ii Collagen ◽  
Cartilage Explants ◽  
Type Ii ◽  
Serum Samples ◽  
Human Cartilage ◽  
Cartilage Formation

N-terminal propeptide of type II collagen (PIINP) is a biomarker reflecting cartilage formation. PIINP exists in two main splice variants termed as type IIA and type IIB collagen NH2-propeptide (PIIANP, PIIBNP). PIIANP has been widely recognized as a cartilage formation biomarker. However, the utility of PIIBNP as a marker in preclinical and clinical settings has not been fully investigated yet. In this study, we aimed to characterize an antibody targeting human PIIBNP and to develop an immunoassay assessing type II collagen synthesis in human blood samples. A high sensitivity electrochemiluminescence immunoassay, hsPRO-C2, was developed using a well-characterized antibody against human PIIBNP. Human cartilage explants from replaced osteoarthritis knees were cultured for ten weeks in the presence of growth factors, insulin-like growth factor 1 (IGF-1) or recombinant human fibroblast growth factor 18 (rhFGF-18). The culture medium was changed every seven days, and levels of PIIBNP, PIIANP, and matrix metalloproteinase 9-mediated degradation of type II collagen (C2M) were analyzed herein. Serum samples from a cross-sectional knee osteoarthritis cohort, as well as pediatric and rheumatoid arthritis samples, were assayed for PIIBNP and PIIANP. Western blot showed that the antibody recognized PIIBNP either as a free fragment or attached to the main molecule. Immunohistochemistry demonstrated that PIIBNP was predominately located in the extracellular matrix of the superficial and deep zones and chondrocytes in both normal and osteoarthritic articular cartilage. In addition, the hsPRO-C2 immunoassay exhibits acceptable technical performances. In the human cartilage explants model, levels of PIIBNP, but not PIIANP and C2M, were increased (2 to 7-fold) time-dependently in response to IGF-1. Moreover, there was no significant correlation between PIIBNP and PIIANP levels when measured in knee osteoarthritis, rheumatoid arthritis, and pediatric serum samples. Serum PIIBNP was significantly higher in controls (KL0/1) compared to OA groups (KL2/3/4, p = 0.012). The hsPRO-C2 assay shows completely different biological and clinical patterns than PIIANP ELISA, suggesting that it may be a promising biomarker of cartilage formation.

Facilitating In Vivo Articular Cartilage Repair by Tissue-Engineered Cartilage Grafts Produced From Auricular Chondrocytes

2017 ◽  
Vol 46 (3) ◽  
pp. 713-727 ◽  
Author(s):  
Chin-Chean Wong ◽  
Chih-Hwa Chen ◽  
Li-Hsuan Chiu ◽  
Yang-Hwei Tsuang ◽  
Meng-Yi Bai ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Articular Cartilage ◽  
Cartilage Repair ◽  
Articular Chondrocytes ◽  
Type Ii Collagen ◽  
Type Ii ◽  
Articular Cartilage Repair ◽  
3 Dimensional ◽  
Cell Conversion

Background: Insufficient cell numbers still present a challenge for articular cartilage repair. Converting heterotopic auricular chondrocytes by extracellular matrix may be the solution. Hypothesis: Specific extracellular matrix may convert the phenotype of auricular chondrocytes toward articular cartilage for repair. Study Design: Controlled laboratory study. Methods: For in vitro study, rabbit auricular chondrocytes were cultured in monolayer for several passages until reaching status of dedifferentiation. Later, they were transferred to chondrogenic type II collagen (Col II)–coated plates for further cell conversion. Articular chondrogenic profiles, such as glycosaminoglycan deposition, articular chondrogenic gene, and protein expression, were evaluated after 14-day cultivation. Furthermore, 3-dimensional constructs were fabricated using Col II hydrogel-associated auricular chondrocytes, and their histological and biomechanical properties were analyzed. For in vivo study, focal osteochondral defects were created in the rabbit knee joints, and auricular Col II constructs were implanted for repair. Results: The auricular chondrocytes converted by a 2-step protocol expressed specific profiles of chondrogenic molecules associated with articular chondrocytes. The histological and biomechanical features of converted auricular chondrocytes became similar to those of articular chondrocytes when cultivated with Col II 3-dimensional scaffolds. In an in vivo animal model of osteochondral defects, the treated group (auricular Col II) showed better cartilage repair than did the control groups (sham, auricular cells, and Col II). Histological analyses revealed that cartilage repair was achieved in the treated groups with abundant type II collagen and glycosaminoglycans syntheses rather than elastin expression. Conclusion: The study confirmed the feasibility of applying heterotopic chondrocytes for cartilage repair via extracellular matrix–induced cell conversion. Clinical Relevance: This study proposes a feasible methodology to convert heterotopic auricular chondrocytes for articular cartilage repair, which may serve as potential alternative sources for cartilage repair.

scholarly journals Association between concentrations of urinary type II collagen neoepitope (uTIINE) and joint space narrowing in patients with knee osteoarthritis

2006 ◽  
Vol 14 (11) ◽  
pp. 1189-1195 ◽  
Author(s):  
M.-P. Hellio Le Graverand ◽  
K.D. Brandt ◽  
S.A. Mazzuca ◽  
B.P. Katz ◽  
R. Buck ◽  
...  
Keyword(s):  
Knee Osteoarthritis ◽  
Joint Space Narrowing ◽  
Type Ii Collagen ◽  
Joint Space ◽  
Type Ii

scholarly journals Cartilage Protective and Chondrogenic Capacity of WIN-34B, a New Herbal Agent, in the Collagenase-Induced Osteoarthritis Rabbit Model and in Progenitor Cells from Subchondral Bone

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Jeong-Eun Huh ◽  
Yeon-Cheol Park ◽  
Byung-Kwan Seo ◽  
Jae-Dong Lee ◽  
Yong-Hyeon Baek ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cartilage Repair ◽  
Subchondral Bone ◽  
Chondrogenic Differentiation ◽  
Rabbit Model ◽  
Type Ii Collagen ◽  
Blue Staining ◽  
Vehicle Group ◽  
Potential Candidate ◽  
Type Ii

We sought to determine the cartilage repair capacity of WIN-34B in the collagenase-induced osteoarthritis rabbit model and in progenitor cells from subchondral bone. The cartilage protective effect of WIN-34B was measured by clinical and histological scores, cartilage area, and proteoglycan and collagen contents in the collagenase-induced osteoarthritis rabbit model. The efficacy of chondrogenic differentiation of WIN-34B was assessed by expression of CD105, CD73, type II collagen, and aggrecanin vivoand was analyzed by the surface markers of progenitor cells, the mRNA levels of chondrogenic marker genes, and the level of proteoglycan, GAG, and type II collagenin vitro. Oral administration of WIN-34B significantly increased cartilage area, and this was associated with the recovery of proteoglycan and collagen content. Moreover, WIN-34B at 200 mg/kg significantly increased the expression of CD105, CD73, type II collagen, and aggrecan compared to the vehicle group. WIN-34B markedly enhanced the chondrogenic differentiation of CD105 and type II collagen in the progenitor cells from subchondral bone. Also, we confirmed that treatment with WIN-34B strongly increased the number of SH-2(CD105) cells and expression type II collagen in subchondral progenitor cells. Moreover, WIN-34B significantly increased proteoglycan, as measured by alcian blue staining; the mRNA level of type IIα1 collagen, cartilage link protein, and aggrecan; and the inhibition of cartilage matrix molecules, such as GAG and type II collagen, in IL-1β-treated progenitor cells. These findings suggest that WIN-34B could be a potential candidate for effective anti-osteoarthritic therapy with cartilage repair as well as cartilage protection via enhancement of chondrogenic differentiation in the collagenase-induced osteoarthritis rabbit model and progenitor cells from subchondral bone.

scholarly journals The Combination of an Inflammatory Peripheral Blood Transcriptome and Imaging Biomarkers Enhance Prediction of Radiographic Progression in Knee Osteoarthritis.

2020 ◽  
Author(s):  
Mukundan Attur ◽  
Svetlana Krasnokutsky ◽  
Hua Zhou ◽  
Jonathan Samuels ◽  
Gregory Chang ◽  
...  
Keyword(s):  
Knee Osteoarthritis ◽  
Peripheral Blood ◽  
Radiographic Progression ◽  
Predictive Biomarkers ◽  
Imaging Biomarkers ◽  
X Ray ◽  
Knee Mri ◽  
Meniscal Lesions ◽  
Symptomatic Knee Osteoarthritis ◽  
Symptomatic Knee

Abstract Objective Predictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores), meniscal lesions, and osteophytes on x-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL transcriptome and these imaging findings at baseline enhanced the prognostic value of either alone. Methods An inflammatory PBL transcriptome (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort, and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by a mJSN cut-point (≥0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC). Results We validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL transcriptome predicted radiographic progression of SKOA after adjustment for age, gender, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semi-quantitative osteophyte score on x-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL transcriptome and medial BML increased the AUC from 0.66 (p=0.004) to 0.75 (p<0.0001) and the odds ratio from 6.31 to 19.10 (p<0.0001) in the combined cohort of 473 subjects. The addition of osteophyte score to BML and PBL transcriptome further increased the predictive value of any single biomarker. A causal analysis demonstrated that the PBL transcriptome and BML independently influenced mJSN. Conclusion The use of the PBL transcriptome together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.

Morphological Assessment of MACI Grafts in Patients with Revision Surgery and Total Joint Arthroplasty

Cartilage ◽  
2019 ◽  
pp. 194760351989075 ◽  
Author(s):  
Aswin Beck ◽  
David Wood ◽  
Christopher J. Vertullo ◽  
Jay Ebert ◽  
Greg Janes ◽  
...  
Keyword(s):  
Cartilage Repair ◽  
Subchondral Bone ◽  
Revision Surgery ◽  
Total Joint Arthroplasty ◽  
Type Ii Collagen ◽  
Joint Arthroplasty ◽  
Type I ◽  
Type Ii ◽  
Osteophyte Formation ◽  
Repair Tissue

Objective To compare the histological and immunohistochemical characteristics of matrix-assisted chondrocyte implantation (MACI) grafts between patients with revision surgery and patients with total joint arthroplasty. Methods Biopsies of MACI grafts from patients with revision and total joint arthroplasty. The graft tissue characteristics and subchondral bone were examined by qualitative histology, ICRS (International Cartilage Repair Society) II scoring and semiquantitative immunohistochemistry using antibodies specific to type I and type II collagen. Results A total of 31 biopsies were available, 10 undergoing total knee arthroplasty (TKA) and 21 patients undergoing revision surgery. Patients in the clinically failed group were significantly older (46.3 years) than patients in the revision group (36.6 years) ( P = 0.007). Histologically, the predominant tissue in both groups was of fibrocartilaginous nature, although a higher percentage of specimens in the revision group contained a hyaline-like repair tissue. The percentages of type I collagen (52.9% and 61.0%) and type II collagen (66.3% and 42.2%) were not significantly different between clinically failed and revised MACI, respectively. The talar dome contained the best and patella the worst repair tissue. Subchondral bone pathology was present in all clinically failed patients and consisted of bone marrow lesions, including edema, necrosis and fibrosis, intralesional osteophyte formation, subchondral bone plate elevation, intralesional osteophyte formation, subchondral bone cyst formation, or combinations thereof. Conclusions MACI grafts in patients with revision and total joint arthroplasty were predominantly fibrocartilage in repair type, did not differ in composition and were histologically dissimilar to healthy cartilage. Clinically failed cases showed evidence of osteochondral unit failure, rather than merely cartilage repair tissue failure. The role of the subchondral bone in relation to pain and failure and the pathogenesis warrants further investigation.

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