Interleukin-6 receptor blockade improves bone healing following ischemic osteonecrosis in adolescent mice

Gen Kuroyanagi; Nobuhiro Kamiya; Ryosuke Yamaguchi; Harry K W Kim

doi:10.1016/j.ocarto.2023.100386

Interleukin-6 receptor blockade improves bone healing following ischemic osteonecrosis in adolescent mice

Osteoarthr Cartil Open. 2023 Aug 2;5(4):100386. doi: 10.1016/j.ocarto.2023.100386. eCollection 2023 Dec.

Authors

Gen Kuroyanagi^{1

2}, Nobuhiro Kamiya^{1

3}, Ryosuke Yamaguchi^{1

4}, Harry K W Kim^{1

5}

Affiliations

¹ Center for Excellence in Hip, Scottish Rite for Children, Dallas, TX 75219, USA.
² Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
³ Faculty of Budo and Sport Studies, Tenri University, Nara 6320071, Japan.
⁴ Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
⁵ Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-8883, USA.

Abstract

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 (IL-6) is significantly increased in the hip synovial fluid of patients with JIO and that articular chondrocytes are primary source of IL-6. Adolescent JIO is particularly challenging to treat and has poor outcome. This study determined if IL-6 receptor blockade prevents bone loss and improves the bone healing in adolescent JIO.

Method: Adolescent mice (12-week-old) surgically induced with JIO were treated with either saline or MR16-1, an IL-6 receptor blocker.

Results: Micro-CT assessment showed significantly increased bone volume (p < 0.001, Cohen's d = 2.0) and trabecular bone thickness (p < 0.001, d = 2.3) after the MR16-1 treatment. Histomorphometric assessment showed significantly increased osteoblast number (p < 0.01, d = 2.3), bone formation rate (p < 0.01, d = 4.3), and mineral apposition rate (p < 0.01, d = 4.1) after the MR16-1 treatment. The number of osteoclasts was unchanged. Histologic assessment showed significantly increased revascularization (p < 0.01) and restoration of the necrotic marrow with new hematopoietic bone marrow (p < 0.01). Vascular endothelial growth factor (VEGF) expression was increased in the revascularized area and the articular cartilage, and in the cultured chondrocytes treated with IL-6 receptor inhibitor.

Conclusion: IL-6 blockade in adolescent mice with JIO enhanced bone formation and revascularization. The findings suggest IL-6 receptor blocker as a potential medical therapy for adolescent JIO.

Keywords: Adolescent ischemic osteonecrosis; Animal model; Cartilage; IL-6 receptor blockade; Legg-Calve-Perthes disease; VEGF.