Interleukin-6 deletion stimulates revascularization and new bone formation following ischemic osteonecrosis in a murine model

Kuroyanagi, Gen; Adapala, Naga Suresh; Yamaguchi, Ryosuke; Kamiya, Nobuhiro; Deng, Zhuo; Aruwajoye, Olumide; Kutschke, Michael; Chen, Elena; Jo, Chan-Hee; Ren, Yinshi; Kim, Harry K.W.

doi:10.1016/j.bone.2018.08.011

Cited by 26 publications

(37 citation statements)

References 36 publications

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“…We and others have previously demonstrated that IL‐6 knockout mice showed similar bone volume to wild‐type control mice. ( 20–22 ) Furthermore, the trabecular bone parameters of non‐necrotic bone in the tocilizumab group did not differ from those of the saline control group, ( 23 ) which is consistent with the clinical findings of tocilizumab‐treated patients, showing that the bone mineral density of the lumbar spine and femoral neck remained stable after 1 year of tocilizumab treatment. ( 24 ) In bone remodeling under the inflammatory conditions, IL‐6 has been shown to promote the formation of osteoclasts and decrease the formation of osteoblasts.…”

Section: Introductionsupporting

confidence: 77%

“…Previously, we showed that IL‐6 inhibition (either through gene deletion or administration of tocilizumab) produced greater new bone formation marked by significant increases in all three parameters studied in a mouse model of ischemic osteonecrosis: the number of osteoblasts, the mineral apposition rate, and the bone formation rate. ( 20,23 ) The varying effects of tocilizumab on bone formation parameters reported in this study compared with the mouse model studies may be attributable to the mouse models having a faster and more robust bone healing response. In the mouse model, completion of bone healing and remodeling is achieved by 4 to 6 weeks post‐ischemia surgery.…”

Section: Discussionmentioning

confidence: 92%

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Anti-Interleukin-6 Therapy Decreases Hip Synovitis and Bone Resorption and Increases Bone Formation Following Ischemic Osteonecrosis of the Femoral Head

Ren

Deng

Gokani

et al. 2020

Journal of Bone and Mineral Research

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Legg‐Calvé‐Perthes disease (LCPD) is a juvenile form of ischemic femoral head osteonecrosis, which produces chronic hip synovitis, permanent femoral head deformity, and premature osteoarthritis. Currently, there is no medical therapy for LCPD. Interleukin‐6 (IL‐6) is significantly elevated in the synovial fluid of patients with LCPD. We hypothesize that IL‐6 elevation promotes chronic hip synovitis and impairs bone healing after ischemic osteonecrosis. We set out to test if anti‐IL‐6 therapy using tocilizumab can decrease hip synovitis and improve bone healing in the piglet model of LCPD. Fourteen piglets were surgically induced with ischemic osteonecrosis and assigned to two groups: the no treatment group (n = 7) and the tocilizumab group (15 to 20 mg/kg, biweekly intravenous injection, n = 7). All animals were euthanized 8 weeks after the induction of osteonecrosis. Hip synovium and femoral heads were assessed for hip synovitis and bone healing using histology, micro‐CT, and histomorphometry. The mean hip synovitis score and the number of synovial macrophages and vessels were significantly lower in the tocilizumab group compared with the no treatment group (p < .0001, p = .01, and p < .01, respectively). Micro‐CT analysis of the femoral heads showed a significantly higher bone volume in the tocilizumab group compared with the no treatment group (p = .02). The histologic assessment revealed a significantly lower number of osteoclasts per bone surface (p < .001) in the tocilizumab group compared with the no treatment group. Moreover, fluorochrome labeling showed a significantly higher percent of mineralizing bone surface (p < .01), bone formation rate per bone surface (p < .01), and mineral apposition rate (p = .04) in the tocilizumab group. Taken together, tocilizumab therapy decreased hip synovitis and osteoclastic bone resorption and increased new bone formation after ischemic osteonecrosis. This study provides preclinical evidence that tocilizumab decreases synovitis and improves bone healing in a large animal model of LCPD. © 2020 American Society for Bone and Mineral Research (ASBMR).

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Section: Introductionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 92%

Anti-Interleukin-6 Therapy Decreases Hip Synovitis and Bone Resorption and Increases Bone Formation Following Ischemic Osteonecrosis of the Femoral Head

Ren

Deng

Gokani

et al. 2020

Journal of Bone and Mineral Research

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“…We previously reported that chondrocytes in the articular cartilage can express several molecules in vivo in addition to IL6 5 , including bone anabolic marker BMP2 19 and vascularization marker VEGF 36 , by responding to a hypoxic change following the ischemic induction. In the global deletion IL6 knockout mice, VEGF expression and revascularization was enhanced in the epiphyseal bone marrow space following ischemic osteonecrosis compared to the wildtype control 11 . In the current study, both BMP2 and VEGF were upregulated while the bone catabolic indicator, RANKL/OPG ratio was downregulated by tocilizumab treatment.…”

Section: Positive Effect Of Tocilizumab On Bone Remodeling Following mentioning

confidence: 89%

“…In bone metabolism, IL6 has been shown to have a negative role by promoting osteoclast activity while decreasing osteoblast activity under chronic inflammatory conditions, such as rheumatoid arthritis (RA) 6e10 . In the condition of osteonecrosis, we recently reported that IL6 deletion stimulates revascularization and new bone formation following ischemic induction in mice 11 . Therefore, it is interesting to move on the preclinical study investigating the effects of IL6 blockade on bone ischemic conditions including JIO.…”

Section: Introductionmentioning

confidence: 99%

IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice

Kamiya

Kuroyanagi

Aruwajoye

et al. 2019

Osteoarthritis and Cartilage

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Keywords:Juvenile ischemic osteonecrosis IL6 Tocilizumab Cartilage anabolism Legg-calve-perthes disease Bone formation s u m m a r y 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 ¼ 0.001, n ¼ 10), thickness (P ¼ 0.007) and number (P ¼ 0.014) and decreased bone separation (P ¼ 0.002) and its deformity (P ¼ 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.

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“…IL-6 is an inflammatory cytokine that exerts pathological effects on inflammatory bone loss ( 101 , 102 ), directly supporting osteoclast formation, stimulating osteoclast differentiation, and accelerating bone resorption ( 103 , 104 ). IL-6 is associated with Th17 cell differentiation ( 105 ), and abnormalities in the IL-6 signaling can disturb the Th17/Treg balance and influence bone homeostasis indirectly ( 106 ).…”

Section: Tcptp In Osteoimmunologymentioning

confidence: 99%

T Cell Protein Tyrosine Phosphatase in Osteoimmunology

et al. 2021

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Osteoimmunology highlights the two-way communication between bone and immune cells. T cell protein tyrosine phosphatase (TCPTP), also known as protein-tyrosine phosphatase non-receptor 2 (PTPN2), is an intracellular protein tyrosine phosphatase (PTP) essential in regulating immune responses and bone metabolism via dephosphorylating target proteins. Tcptp knockout in systemic or specific immune cells can seriously damage the immune function, resulting in bone metabolism disorders. This review provided fresh insights into the potential role of TCPTP in osteoimmunology. Overall, the regulation of osteoimmunology by TCPTP is extremely complicated. TCPTP negatively regulates macrophages activation and inflammatory factors secretion to inhibit bone resorption. TCPTP regulates T lymphocytes differentiation and T lymphocytes-related cytokines signaling to maintain bone homeostasis. TCPTP is also expected to regulate bone metabolism by targeting B lymphocytes under certain time and conditions. This review offers a comprehensive update on the roles of TCPTP in osteoimmunology, which can be a promising target for the prevention and treatment of inflammatory bone loss.

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Interleukin-6 deletion stimulates revascularization and new bone formation following ischemic osteonecrosis in a murine model

Cited by 26 publications

References 36 publications

Anti-Interleukin-6 Therapy Decreases Hip Synovitis and Bone Resorption and Increases Bone Formation Following Ischemic Osteonecrosis of the Femoral Head

Anti-Interleukin-6 Therapy Decreases Hip Synovitis and Bone Resorption and Increases Bone Formation Following Ischemic Osteonecrosis of the Femoral Head

IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice

T Cell Protein Tyrosine Phosphatase in Osteoimmunology

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