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DTI can monitor changes in articular cartilage after a mechanically induced injury
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Abstracts / Osteoarthritis and Cartilage 24 (2016) S63eS534
Figure 1. Bone histomorphometry obtained via micro-CT scanning of burr-hole fractures at day 0, week 1, 2 and 4 for C57BL/6 and p21-/- mice. *p<0.05.
Figure 2. Cartilage regeneration in p21-/- mice. A) Uninjured cartilage (histological grading score ¼ 14), B) 4 week FTCD in C57 mouse (histological grade score ¼ 2), C) 4 week FTCD in p21 knockout mouse showing smooth surface and matrix regeneration (histological grade score ¼ 10).
Conclusions: p21 is a cyclin dependent kinase inhibitor that has been implicated in cell proliferation; inhibition of which leads to enhanced proliferation of cells. A mouse model where p21 is inhibited has exhibited enhanced regenerative capacity after injury to the bone and cartilage. The mouse model will provide a suitable environment to probe the specific relationship between the subchondral bone and cartilage after an injury. In the future, bone and cartilage specific drivers will be combined with conditional p21-/- mice to tease out the role of bone versus cartilage repair in the onset and progression of OA. Delineating the potential role of subchondral bone in the onset and progression of OA will enable us to develop therapies that cater to the subchondral bone rather than solely the cartilage. 608 DTI CAN MONITOR CHANGES IN ARTICULAR CARTILAGE AFTER A MECHANICALLY INDUCED INJURY U. Ferizi, I. Rossi, J. Teplensky, Y. Lee, M. Lendhey, T. Kirsch, O. Kennedy, J. Bencardino, J. Raya. New York Univ. Sch. of Med., New York, NY, USA Purpose: Changes in cartilage after injury can be captured by DTI, which is sensitive to PG and collagen. Using clinical scanners, we test how well DTI detects changes in articular cartilage after mechanical injury. Methods: Cartilage-on-bone samples were harvested from two patients who underwent knee replacement. From the macroscopically intact areas we drilled nine 4-mm-diameter cylindrical samples. Histology before and after injury(Week0/Week2): Serial histological sectioning was performed with safranin-O, and the samples were OARSI scored.
Biomechanics before and after injury(Week0/Week2): A repetitive stress-relaxation test with a maximum strain of 20% of cartilage thickness was conducted (in four 5%-steps). Cartilage injury was induced at three levels: three at 0N (controls), three at 120N (mild), and three at 190 N (severe)[V.Morel,2004. Cartilage injury by ramp compression... J.Orth.Res.]. The test was repeated two weeks after injury. We use a standard model to fit the stress-relaxation curves [J.J.Sarver et al.2003. Methods for quasilinear viscoelastic modeling... J.Biomech.Eng.]. DTI imaging on Week0/Week1/Week2: We used a 3T clinical scanner, with an in-house built 4 cm butterfly coil and a RAISED sequence for DTI. We set TR/TE¼1500/49 ms, resolution¼(0.18x0.18 mm2)x1.2mm, BW¼300 Hz/pixel, 360 spokes, D¼19ms and d¼14.45ms. The 2h MRI protocol consisted of 6-dir b¼300s/mm2 shells. We then evaluate the correlations between the changes in MD/FA, histology and biomechanics. Results: Fig.1-left shows some histology images. The OARSI score for native baseline cartilages was low, at an average of 0.75 ± 0.36. There was no difference in the baseline OARSI score between the severe (0.61 ± 0.30), mild (0.88 ± 0.41) and negative control (0.77 ± 0.16) groups. The score Week-0-2 change for the severely injured samples was 2.53 ± 1.30, for the mildly injured was 0.64 ± 0.62, and for the controls it was 0.37 ± 0.25. The DTI maps (fig.1-right) at Week 0/Week2 give the average MD values for Controls 1.34/1.31, for Mild Injury 1.28/1.38, and for Severe Injury 1.36/1.54 (mm2/ms units); for FA they were 0.25/0.3, 0.30/0.31 and 0.25/ 0.19, respectively. Fig.2 shows the stress relaxation curves. For severe injury, the slopes ratio was 2.99 ± 0.71, for mild injury1.89 ± 0.39, for controls 0.99 ± 0.14. Fig.3 shows the ability for both (MD/FA) DTI biomarkers to differentiate between the three time points of the severe injury case. As expected, for the severely injured samples, the MD increases in time, whereas FA decreases. The MD achieves a (statistically-significant) group difference for both Week-1-2, while FA only for Week-2. On average, the severe samples group indicate a Week-0-2 change in bulk MD of 0.15 ± 0.08 mm2/ms and in FA of -0.06 ± 0.03. In figure 4, the table gives correlations between before-and-after changes in DTI (MD/FA), histology (OARSI) and biomechanics (‘relative’), as well as all the pooled measurements (‘absolute’). For MDbiomechanics, the only significant correlation is for bulk and deep layer parameters. In relative MD vs. histology, only the surface correlation is significant. This is consistent with the known pattern of cartilage degradation, where the surface is the first to degrade, and the deterioration later propagating down the cartilage. In absolute MD vs. histology, all except deep layer correlations are significant. Figure 5 shows that DTI correlates with both biomechanics and histology. The first subplot shows the relation between the change in histology against the change in the biomechanics slopes. The next two subplots show the MD against biomechanics and the histology. As indicated from the result in table 1, only the MD vs. biomechanics results are statistically significant. Though we do not see significance for the decreasing week-1 FA, there is a clear trend towards lower values. Conclusions: DTI biomarkers promise real-time indicators in the diagnosis and the monitoring of the disease. This study will help us to discriminate not just damaged from non-damaged tissue but also capture early signs of damage.
Abstracts / Osteoarthritis and Cartilage 24 (2016) S63eS534
S369
Purpose: To investigate the cross-sectional association between serum levels of adipocytokines and infrapatellar fat pad (IPFP) size and signal intensity alternations in patients with knee osteoarthritis (OA). Methods: 170 subjects with symptomatic knee OA (mean 55.4 years, range 34 to 74, 88.2% females) were included. IPFP volume was measured on T1-weighted SPGR images and was computed by software program. IPFP signal intensity alteration (grade 03) was assessed on T2-weighted MR images. Serum IL-17, adiponectin and resistin levels were measured using ELISA. Results: In multivariable analyses, serum IL-17 was negatively associated with IPFP volume (b: 0.185; 95%CI: 0.337 to 0.034) but positively associated with the severity of IPFP signal intensity alteration [odd ratio (OR): 1.23; 95%CI: 1.06 to 1.42] after adjustment for age, sex, weight and height. Serum adiponectin was positively associated with IPFP volume (b: 0.016; 95%CI: 0.001 to 0.032) but negatively associated with IPFP signal intensity alteration (OR: 0.99; 95%CI: 0.98 to 1.00) after adjustment for covariates. Resistin was positively associated with IPFP signal intensity alteration (OR: 1.13; 95%CI: 1.04 to 1.23) but not with IPFP volume. The significant associations of adiponectin or resistin disappeared after further adjustment for IL-17; in contrast, the significant associations of IL-17 remained after further adjustment for adiponectin. Conclusions: While serum IL-17 was associated with reduced IPFP volume and increased abnormal signal intensity alteration, the associations of adiponectin were opposite and of resistin were similar and were largely through IL-17. These suggest that serum adipocytokines may play roles in IPFP changes of knee OA. 610 ASSOCIATION BETWEEN MRI-DETECTED OSTEOPHYTES AND CHANGES IN KNEE PAIN AND STRUCTURES IN OLDER ADULTS: A COHORT STUDY Z. Zhu, Jr., L.L. Laslett, X. Jin, W. Han, B. Antony, X. Wang, F. Cituttini, G. Jones, C. Ding. Menzies Inst. for Med. Res., Hobart, Australia
609 SERUM LEVELS OF INTERLEUKIN-17 AND ADIPONECTIN ARE ASSOCIATED WITH INFRAPATELLAR FAT PAD VOLUME AND SIGNAL INTENSITY ALTERNATION IN PATIENTS WITH KNEE OSTEOARTHRITIS K. Wang y, J. Xu y, J. Cai y, S. Zheng y, W. Han z, B. Antony x, C. Ding x. y The first affiliated Hosp. of Anhui Med. Univ., Hefei, China; z Menzies Inst. for Med. Res., Univ. of Tasmania, Hobart, Australia; x Menzies Inst. for Med. Res., Univ. of Tasmania, Hobart, Australia
Purpose: Osteophyte (OP) formation is one of the hallmarks of osteoarthritis (OA), and early detection of OP formation can be of diagnostic value. Magnetic resonance imaging can visualize OP at locations that are not easily accessed by conventional radiography and at greater sensitivity than radiographs for detection of early formation of OP. Although some studies have examined relationships between MRI-detected OP and clinical features of knee OA, longitudinal studies are rare. Therefore, our study aims to describe the cross-sectional and longitudinal associations between MRI-detected OP and knee pain and structural changes in older adults; and to evaluate the predictive ability of preradiographic OP for knee pain and structural changes. Methods: 410 participants (mean age 62 years, 50% female) were randomly selected from local community at baseline and were followed up over 2.6 years. T1- or T2-weighted fat suppressed magnetic resonance imaging (MRI) was used to assess knee OP, cartilage volume, cartilage defects and bone marrow lesions (BMLs) at baseline and after 2.6 years. Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis (WOMAC) Index questionnaire at baseline and after 5 year. Radiographic osteoarthritis (ROA) was assessed at baseline with a standing anteroposterior semiflexed radiograph scored using the Osteoarthritis Research Society International atlas. Analyses were performed using linear regression models and log-binominal regression models. Results: 86.6% of participants had MRI-detected OPs at baseline, while only 10% of participants with radiographic OPs. Cross-sectionally, MRIdetected OPs at medial tibiofemoral, lateral tibiofemoral and patellar compartments were significantly and site-specifically associated with a higher prevalence of cartilage defects and BMLs, and reduced cartilage volume after adjusted for common covariates (all p<0.01). MRI-detected OPs in patellar, medial tibiofemoral, lateral tibiofemoral and whole compartments were significantly associated with higher prevalence of weight bearing knee pain (p<0.01, p<0.01, p¼0.03 and p¼0.02, respectively); whereas significant association with non-weight bearing pain was only observed in medial tibiofemoral compartment (p¼0.02), after adjustment for relevant covariates. Longitudinally, baseline MRIdetected OP site-specifically predicted increases in cartilage defects and BMLs and loss of cartilage volume in total knee, medial tibiofemoral and lateral tibiofemoral compartments, after adjusted for common covariates and other structures (both p<0.01). Compared to participants without any OP, participants with pre-radiographic OP (with MRI-
Abstracts / Osteoarthritis and Cartilage 24 (2016) S63eS534
Figure 1. Bone histomorphometry obtained via micro-CT scanning of burr-hole fractures at day 0, week 1, 2 and 4 for C57BL/6 and p21-/- mice. *p<0.05.
Figure 2. Cartilage regeneration in p21-/- mice. A) Uninjured cartilage (histological grading score ¼ 14), B) 4 week FTCD in C57 mouse (histological grade score ¼ 2), C) 4 week FTCD in p21 knockout mouse showing smooth surface and matrix regeneration (histological grade score ¼ 10).
Conclusions: p21 is a cyclin dependent kinase inhibitor that has been implicated in cell proliferation; inhibition of which leads to enhanced proliferation of cells. A mouse model where p21 is inhibited has exhibited enhanced regenerative capacity after injury to the bone and cartilage. The mouse model will provide a suitable environment to probe the specific relationship between the subchondral bone and cartilage after an injury. In the future, bone and cartilage specific drivers will be combined with conditional p21-/- mice to tease out the role of bone versus cartilage repair in the onset and progression of OA. Delineating the potential role of subchondral bone in the onset and progression of OA will enable us to develop therapies that cater to the subchondral bone rather than solely the cartilage. 608 DTI CAN MONITOR CHANGES IN ARTICULAR CARTILAGE AFTER A MECHANICALLY INDUCED INJURY U. Ferizi, I. Rossi, J. Teplensky, Y. Lee, M. Lendhey, T. Kirsch, O. Kennedy, J. Bencardino, J. Raya. New York Univ. Sch. of Med., New York, NY, USA Purpose: Changes in cartilage after injury can be captured by DTI, which is sensitive to PG and collagen. Using clinical scanners, we test how well DTI detects changes in articular cartilage after mechanical injury. Methods: Cartilage-on-bone samples were harvested from two patients who underwent knee replacement. From the macroscopically intact areas we drilled nine 4-mm-diameter cylindrical samples. Histology before and after injury(Week0/Week2): Serial histological sectioning was performed with safranin-O, and the samples were OARSI scored.
Biomechanics before and after injury(Week0/Week2): A repetitive stress-relaxation test with a maximum strain of 20% of cartilage thickness was conducted (in four 5%-steps). Cartilage injury was induced at three levels: three at 0N (controls), three at 120N (mild), and three at 190 N (severe)[V.Morel,2004. Cartilage injury by ramp compression... J.Orth.Res.]. The test was repeated two weeks after injury. We use a standard model to fit the stress-relaxation curves [J.J.Sarver et al.2003. Methods for quasilinear viscoelastic modeling... J.Biomech.Eng.]. DTI imaging on Week0/Week1/Week2: We used a 3T clinical scanner, with an in-house built 4 cm butterfly coil and a RAISED sequence for DTI. We set TR/TE¼1500/49 ms, resolution¼(0.18x0.18 mm2)x1.2mm, BW¼300 Hz/pixel, 360 spokes, D¼19ms and d¼14.45ms. The 2h MRI protocol consisted of 6-dir b¼300s/mm2 shells. We then evaluate the correlations between the changes in MD/FA, histology and biomechanics. Results: Fig.1-left shows some histology images. The OARSI score for native baseline cartilages was low, at an average of 0.75 ± 0.36. There was no difference in the baseline OARSI score between the severe (0.61 ± 0.30), mild (0.88 ± 0.41) and negative control (0.77 ± 0.16) groups. The score Week-0-2 change for the severely injured samples was 2.53 ± 1.30, for the mildly injured was 0.64 ± 0.62, and for the controls it was 0.37 ± 0.25. The DTI maps (fig.1-right) at Week 0/Week2 give the average MD values for Controls 1.34/1.31, for Mild Injury 1.28/1.38, and for Severe Injury 1.36/1.54 (mm2/ms units); for FA they were 0.25/0.3, 0.30/0.31 and 0.25/ 0.19, respectively. Fig.2 shows the stress relaxation curves. For severe injury, the slopes ratio was 2.99 ± 0.71, for mild injury1.89 ± 0.39, for controls 0.99 ± 0.14. Fig.3 shows the ability for both (MD/FA) DTI biomarkers to differentiate between the three time points of the severe injury case. As expected, for the severely injured samples, the MD increases in time, whereas FA decreases. The MD achieves a (statistically-significant) group difference for both Week-1-2, while FA only for Week-2. On average, the severe samples group indicate a Week-0-2 change in bulk MD of 0.15 ± 0.08 mm2/ms and in FA of -0.06 ± 0.03. In figure 4, the table gives correlations between before-and-after changes in DTI (MD/FA), histology (OARSI) and biomechanics (‘relative’), as well as all the pooled measurements (‘absolute’). For MDbiomechanics, the only significant correlation is for bulk and deep layer parameters. In relative MD vs. histology, only the surface correlation is significant. This is consistent with the known pattern of cartilage degradation, where the surface is the first to degrade, and the deterioration later propagating down the cartilage. In absolute MD vs. histology, all except deep layer correlations are significant. Figure 5 shows that DTI correlates with both biomechanics and histology. The first subplot shows the relation between the change in histology against the change in the biomechanics slopes. The next two subplots show the MD against biomechanics and the histology. As indicated from the result in table 1, only the MD vs. biomechanics results are statistically significant. Though we do not see significance for the decreasing week-1 FA, there is a clear trend towards lower values. Conclusions: DTI biomarkers promise real-time indicators in the diagnosis and the monitoring of the disease. This study will help us to discriminate not just damaged from non-damaged tissue but also capture early signs of damage.
Abstracts / Osteoarthritis and Cartilage 24 (2016) S63eS534
S369
Purpose: To investigate the cross-sectional association between serum levels of adipocytokines and infrapatellar fat pad (IPFP) size and signal intensity alternations in patients with knee osteoarthritis (OA). Methods: 170 subjects with symptomatic knee OA (mean 55.4 years, range 34 to 74, 88.2% females) were included. IPFP volume was measured on T1-weighted SPGR images and was computed by software program. IPFP signal intensity alteration (grade 03) was assessed on T2-weighted MR images. Serum IL-17, adiponectin and resistin levels were measured using ELISA. Results: In multivariable analyses, serum IL-17 was negatively associated with IPFP volume (b: 0.185; 95%CI: 0.337 to 0.034) but positively associated with the severity of IPFP signal intensity alteration [odd ratio (OR): 1.23; 95%CI: 1.06 to 1.42] after adjustment for age, sex, weight and height. Serum adiponectin was positively associated with IPFP volume (b: 0.016; 95%CI: 0.001 to 0.032) but negatively associated with IPFP signal intensity alteration (OR: 0.99; 95%CI: 0.98 to 1.00) after adjustment for covariates. Resistin was positively associated with IPFP signal intensity alteration (OR: 1.13; 95%CI: 1.04 to 1.23) but not with IPFP volume. The significant associations of adiponectin or resistin disappeared after further adjustment for IL-17; in contrast, the significant associations of IL-17 remained after further adjustment for adiponectin. Conclusions: While serum IL-17 was associated with reduced IPFP volume and increased abnormal signal intensity alteration, the associations of adiponectin were opposite and of resistin were similar and were largely through IL-17. These suggest that serum adipocytokines may play roles in IPFP changes of knee OA. 610 ASSOCIATION BETWEEN MRI-DETECTED OSTEOPHYTES AND CHANGES IN KNEE PAIN AND STRUCTURES IN OLDER ADULTS: A COHORT STUDY Z. Zhu, Jr., L.L. Laslett, X. Jin, W. Han, B. Antony, X. Wang, F. Cituttini, G. Jones, C. Ding. Menzies Inst. for Med. Res., Hobart, Australia
609 SERUM LEVELS OF INTERLEUKIN-17 AND ADIPONECTIN ARE ASSOCIATED WITH INFRAPATELLAR FAT PAD VOLUME AND SIGNAL INTENSITY ALTERNATION IN PATIENTS WITH KNEE OSTEOARTHRITIS K. Wang y, J. Xu y, J. Cai y, S. Zheng y, W. Han z, B. Antony x, C. Ding x. y The first affiliated Hosp. of Anhui Med. Univ., Hefei, China; z Menzies Inst. for Med. Res., Univ. of Tasmania, Hobart, Australia; x Menzies Inst. for Med. Res., Univ. of Tasmania, Hobart, Australia
Purpose: Osteophyte (OP) formation is one of the hallmarks of osteoarthritis (OA), and early detection of OP formation can be of diagnostic value. Magnetic resonance imaging can visualize OP at locations that are not easily accessed by conventional radiography and at greater sensitivity than radiographs for detection of early formation of OP. Although some studies have examined relationships between MRI-detected OP and clinical features of knee OA, longitudinal studies are rare. Therefore, our study aims to describe the cross-sectional and longitudinal associations between MRI-detected OP and knee pain and structural changes in older adults; and to evaluate the predictive ability of preradiographic OP for knee pain and structural changes. Methods: 410 participants (mean age 62 years, 50% female) were randomly selected from local community at baseline and were followed up over 2.6 years. T1- or T2-weighted fat suppressed magnetic resonance imaging (MRI) was used to assess knee OP, cartilage volume, cartilage defects and bone marrow lesions (BMLs) at baseline and after 2.6 years. Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis (WOMAC) Index questionnaire at baseline and after 5 year. Radiographic osteoarthritis (ROA) was assessed at baseline with a standing anteroposterior semiflexed radiograph scored using the Osteoarthritis Research Society International atlas. Analyses were performed using linear regression models and log-binominal regression models. Results: 86.6% of participants had MRI-detected OPs at baseline, while only 10% of participants with radiographic OPs. Cross-sectionally, MRIdetected OPs at medial tibiofemoral, lateral tibiofemoral and patellar compartments were significantly and site-specifically associated with a higher prevalence of cartilage defects and BMLs, and reduced cartilage volume after adjusted for common covariates (all p<0.01). MRI-detected OPs in patellar, medial tibiofemoral, lateral tibiofemoral and whole compartments were significantly associated with higher prevalence of weight bearing knee pain (p<0.01, p<0.01, p¼0.03 and p¼0.02, respectively); whereas significant association with non-weight bearing pain was only observed in medial tibiofemoral compartment (p¼0.02), after adjustment for relevant covariates. Longitudinally, baseline MRIdetected OP site-specifically predicted increases in cartilage defects and BMLs and loss of cartilage volume in total knee, medial tibiofemoral and lateral tibiofemoral compartments, after adjusted for common covariates and other structures (both p<0.01). Compared to participants without any OP, participants with pre-radiographic OP (with MRI-