Osteoclast: The novel whistleblower in osteonecrosis of the femoral head

Osteonecrosis of the femoral head (ONFH) is a common but refractory orthopedic disease characterized by femoral head ischemia and subchondral bone destruction. Globally, the prevalence of ONFH is relatively high and still increasing, affecting mainly younger adults and without satisfactory early diagnostic markers and intervention. Dysregulated bone homeostasis due to various etiologies as well as osteoimmune interactions under pathological conditions lead to ONFH pathogenesis. Although progress has been made in studies focusing on compromised vascular circulation, bone marrow mesenchymal stem cells (BMSCs) damage, and dysregulation of osteogenesis and chondrogenesis, recent works have highlighted the importance of osteoclast (OC) in the progression of ONFH pathology, especially as a hub for the multi-directional effect of the immune system on bone metabolism. A full understanding of OC behaviors and inducing factors help in identifying early diagnosis and specific therapies. Along those lines, numerous works have defined the essential role of OC in the alternation of ONFH staging as a whistleblower, not only demonstrating its typical bone-resorbing machinery but also describing the cellular and cytokine-mediated dynamic interactions that are related to specific etiologies and pathological conditions. In this review, we discuss emerging discoveries and concepts in the context of existing work and highlight the OC as a central actor in contributing to the progression of ONFH.