TY - JOUR
T1 - IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice
AU - Kamiya, N.
AU - Kuroyanagi, G.
AU - Aruwajoye, O.
AU - Kim, Harry K
N1 - Funding Information:
This work was supported by the Intramural Research Program from Texas Scottish Rite Hospital for Children (H.K.) and JPJS KAKENHI (N.K. 15K08437). We thank Amanda McLerran for animal care and surgical assistance, Reuel Cornelia and Richard Banlaygas for histological preparation, Jo Chan-Hee for advice on statistical analysis, and Ila Oxendine for technical assistance.
Publisher Copyright:
© 2018 Osteoarthritis Research Society International
PY - 2019/2
Y1 - 2019/2
N2 - Objective: Juvenile ischemic osteonecrosis (JIO) of the femoral head is one of the most serious hip disorders causing a permanent deformity of the femoral head in childhood. We recently reported that interleukin 6 (IL6) is predominantly increased in the hip synovial fluid of patients with JIO and that articular chondrocytes are primary source of IL6. This study investigated whether an inhibition of IL6 receptor improves cartilage preservation and bone healing in JIO. Method: A small animal model (i.e., 6-week-old mouse) of JIO was treated with either saline or tocilizumab, an IL6 receptor blocker, for 6 weeks. Results: TUNEL-positive chondrocytes in the articular cartilage were reduced by the tocilizumab treatment, concomitant with the increase in cartilage matrix. The levels of a cartilage anabolic marker Sox9 was significantly increased in the articular cartilage of mice treated with tocilizumab. Micro-CT assessment showed tocilizumab treatment significantly increased trabecular epiphyseal bone volume (P = 0.001, n = 10), thickness (P = 0.007) and number (P = 0.014) and decreased bone separation (P = 0.002) and its deformity (P = 0.003). A bone formation marker, BMP2, and an angiogenic marker, vascular endothelial growth factor (VEGF), were both significantly increased by tocilizumab treatment under hypoxia using human chondrocytes while the bone resorption marker, RANKL/OPG ratio, was reduced. Conclusion: Tocilizumab treatment following ischemic osteonecrosis has cartilage anabolic effect and increases bone volume in JIO mouse model. The findings lead to a possible application of tocilizumab for preclinical study using a large animal model of JIO and a clinical trial to validate this treatment.
AB - Objective: Juvenile ischemic osteonecrosis (JIO) of the femoral head is one of the most serious hip disorders causing a permanent deformity of the femoral head in childhood. We recently reported that interleukin 6 (IL6) is predominantly increased in the hip synovial fluid of patients with JIO and that articular chondrocytes are primary source of IL6. This study investigated whether an inhibition of IL6 receptor improves cartilage preservation and bone healing in JIO. Method: A small animal model (i.e., 6-week-old mouse) of JIO was treated with either saline or tocilizumab, an IL6 receptor blocker, for 6 weeks. Results: TUNEL-positive chondrocytes in the articular cartilage were reduced by the tocilizumab treatment, concomitant with the increase in cartilage matrix. The levels of a cartilage anabolic marker Sox9 was significantly increased in the articular cartilage of mice treated with tocilizumab. Micro-CT assessment showed tocilizumab treatment significantly increased trabecular epiphyseal bone volume (P = 0.001, n = 10), thickness (P = 0.007) and number (P = 0.014) and decreased bone separation (P = 0.002) and its deformity (P = 0.003). A bone formation marker, BMP2, and an angiogenic marker, vascular endothelial growth factor (VEGF), were both significantly increased by tocilizumab treatment under hypoxia using human chondrocytes while the bone resorption marker, RANKL/OPG ratio, was reduced. Conclusion: Tocilizumab treatment following ischemic osteonecrosis has cartilage anabolic effect and increases bone volume in JIO mouse model. The findings lead to a possible application of tocilizumab for preclinical study using a large animal model of JIO and a clinical trial to validate this treatment.
KW - Bone formation
KW - Cartilage anabolism
KW - IL6
KW - Juvenile ischemic osteonecrosis
KW - Legg-calve-perthes disease
KW - Tocilizumab
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U2 - 10.1016/j.joca.2018.10.010
DO - 10.1016/j.joca.2018.10.010
M3 - Article
C2 - 30404032
AN - SCOPUS:85057030625
SN - 1063-4584
VL - 27
SP - 326
EP - 335
JO - Osteoarthritis and Cartilage
JF - Osteoarthritis and Cartilage
IS - 2
ER -