Steroid-induced osteonecrosis of the femoral head reveals enhanced reactive oxygen species and hyperactive osteoclasts

Abstract

Steroid-induced osteonecrosis of the femoral head (ONFH) is a progressive bone disorder which typically results in femoral head collapse and hip joint dysfunction. It is well-accepted that abnormal osteoclast activity contributes to loss of bone structural integrity and subchondral fracture in ONFH. However, the pathophysiologic mechanisms underlying the recruitment and hyperactivation of osteoclasts in ONFH remain incompletely understood. We assessed the changes of reactive oxygen species (ROS) level and subsequent osteoclast alterations in steroid-induced osteonecrotic femoral heads from both patients and rat ONFH models. When compared with healthy neighboring bone, the necrotic region of human femoral head was characterized by robust up-regulated expression of osteoclast-related proteins [cathepsin K and tartrate-resistant acid phosphatase(TRAP)] but pronounced down-regulation of antioxidant enzymes (catalase, γ-glutamylcysteine synthetase [γ-GCSc], and superoxide dismutase 1 [SOD1]). In addition, the ratio of TNFSF11 (encoding RANKL)/TNFRSF11B (encoding OPG) was increased within the necrotic bone. Consistently, in rat ONFH models induced by methylprednisolone (MPSL) and imiquimod (IMI), significant bone loss in the femoral head was observed, attributable to increased numbers of TRAP positive osteoclasts. Furthermore, the decreased expression of antioxidant enzymes observed by immunoblotting was accompanied by increased ex-vivo ROS fluorescence signals of dihydroethidium (DHE) in rat ONFH models. Therefore, this study lends support to the rationale that antioxidant agents may be a promising therapeutic avenue to prevent or mitigate the progression of steroid-induced ONFH by inhibiting ROS level and hyperactive osteoclasts.

Identification of Candidate Genes Associated with Steroid-Induced Osteonecrosis of The Femoral Head by Bioinformatics Based on GEO Database

“…The previous studies have demonstrated that steroid is an established risk factor of osteonecrosis of the femoral head (ONFH) [4][5][6] . Moreover, numerous researches have proved that the mechanism of steroid-induced osteonecrosis of the femoral head (SONFH) including oxidative stress 7 , osteoclasts activation 8 , bone formation and resorption 9 , et al SONFH most have been diagnosed by magnetic resonance imaging (MRI) 5 . However, the reliable biomarkers of SONFH remained unknown.…”

Combined Pharmacotherapy with Alendronate and Desferoxamine Regulate the Bone Resorption and Bone Regeneration for Preventing Glucocorticoids-Induced Osteonecrosis of the Femoral Head

“…In fact, OC is one of the most important factors in bone remodeling, which contributes to absorb the dead bone and promotes bone regeneration [ 26 ]. However, with effects of long excessive GCs, OCs are overactivated and the bone loss is increased even exceeding bone formation; therefore, the normal bone structure is destroyed and the femoral head collapsed [ 27 ]. Bisphosphonate is effective in inhibiting the activity of OCs and has been used to treat osteoporosis, Paget's disease, and fibrous dysplasia, etc.…”

Maackiain dampens osteoclastogenesis via attenuating RANKL‐stimulated NF‐κB signalling pathway and NFATc1 activity

“…Over‐activation of osteoclasts can lead to osteolytic conditions such as Paget's disease, osteoporosis and osteonecrosis 3‐5 . The present methods of treating osteolytic diseases are limited with potential adverse effects 6,29 .…”

“…Osteolytic diseases are caused by the hyperactive differentiation and resorbing function of osteoclasts 1 which are coupled with osteoblasts to maintain healthy bone homeostasis 2 . Enhanced bone resorption will result in osteolytic conditions such as osteoporosis, Paget's disease and osteonecrosis 3‐5 . Especially in postmenopausal women with osteoporosis due to oestrogen deficiency, serious complications such as fragility fractures could occur under slight external force, which imposes a huge burden socio‐economically 3 .…”