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

Abstract

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).

A GP130-Targeting Small Molecule, LMT-28, Reduces LPS-Induced Bone Resorption around Implants in Diabetic Models by Inhibiting IL-6/GP130/JAK2/STAT3 Signaling

“…Second, IL-6 directly stimulates osteoclasts and participates in the differentiation and function of osteoclasts [20]. Therefore, some studies believe that inhibiting the high expression of IL-6 or decreasing the function of IL-6 will reduce bone resorption [21].…”

The Dynamic Feature of Macrophage M1/M2 Imbalance Facilitates the Progression of Non-Traumatic Osteonecrosis of the Femoral Head

“…Interestingly, our results are similar to those reported for patients with drug-induced osteonecrosis, who show increased IL-6 levels in the local lesion and/or in the circulation ( Bagan et al, 2014 ; Badros et al, 2021 ; Paschalidi et al, 2021 ). In the piglet model of ischemic ONFH, IL-6 inhibitors inhibit osteoclastogenesis and delay progression of osteonecrosis ( Ren et al, 2021 ), further highlighting the important role of IL-6 in the chronic inflammation of osteonecrosis. The increased accumulation of IL-6 at the site of injury most likely leads to increased levels in the circulation: indeed, the level of IL-6 in plasma was over five times in progressive-stage NONFH than in osteoarthritis.…”

Obesity impairs revascularization and bone healing in a mouse model of osteonecrosis

“…After weaning at the age of 4 weeks, 27 mice were randomly divided into three groups (ND: normal diet, n = 8; HFD: high-fat diet, n = 11; WL: weight loss, n = 8) (Figure 1A) as described in our previous studies. 23,24 The sample size was selected based on the previous studies. 20,25,26 During the age of week 4-12, mice in the ND group were fed with the ND (2916, 12% Kcal fat) (ENVIGO), and mice in the HFD and the WL groups were fed with the HFD (TD.06414, 60% Kcal fat) (ENVIGO).…”