Key Triggers of Osteoclast-Related Diseases and Available Strategies for Targeted Therapies: A Review

Abstract

Osteoclasts, the only cells with bone resorption functions in vivo, maintain the balance of bone metabolism by cooperating with osteoblasts, which are responsible for bone formation. Excessive activity of osteoclasts causes many diseases such as osteoporosis, periprosthetic osteolysis, bone tumors, and Paget’s disease. In contrast, osteopetrosis results from osteoclast deficiency. Available strategies for combating over-activated osteoclasts and the subsequently induced diseases can be categorized into three approaches: facilitating osteoclast apoptosis, inhibiting osteoclastogenesis, and impairing bone resorption. Bisphosphonates are representative molecules that function by triggering osteoclast apoptosis. New drugs, such as tumor necrosis factor and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (e.g., denosumab) have been developed for targeting the receptor activator of nuclear factor kappa-B /RANKL/osteoprotegerin system or CSF-1/CSF-1R axis, which play critical roles in osteoclast formation. Furthermore, vacuolar (H+)-ATPase inhibitors, cathepsin K inhibitors, and glucagon-like peptide 2 impair different stages of the bone resorption process. Recently, significant achievements have been made in this field. The aim of this review is to provide an updated summary of the current progress in research involving osteoclast-related diseases and of the development of targeted inhibitors of osteoclast formation.

Artemisinin-Daumone Hybrid Inhibits Cancer Cell-Mediated Osteolysis by Targeting Cancer Cells and Osteoclasts

“…Mature osteoclasts cause severe bone resorption by secreting proteases and protons [42,43]. Inhibitors of MMPs and cathepsin K have been considered as promising therapeutic candidates for osteoclast-related diseases [44,45]. ARTD at noncytotoxic concentrations remarkably inhibited RANKL-induced osteoclast formation, mature osteoclast-mediated pit formation, and MMP-9 and cathepsin K secretion from mature osteoclasts.…”

Dracorhodin perchlorate inhibits osteoclastogenesis through repressing RANKL‐stimulated NFATc1 activity

“…Over‐activation of osteoclast function is one of the mechanisms causing osteolytic diseases, such as osteoporosis, osteonecrosis and Paget's disease . Current treatments of these diseases are limited, expensive and would cause various side effects .…”

Inhibition of Osteoclastogenesis by the RNA-Binding Protein QKI5: a Novel Approach to Protect from Bone Resorption

“…Because CSF1‐R and RANK‐L receptor are key molecules that regulate osteoclastogenesis, numerous treatments have been developed to specifically inhibit their expression. Because RANK/RANKL hyperstimulation is at the origin of most OC‐related diseases, several strategies have been adopted to inhibit this pathway. An anti‐RANKL antibody (denosumab) has been developed to block the interaction of RANKL with RANK and inhibits osteoclastogenesis, thus limiting the incidence of bone fracture and increasing bone mineral density without targeting inflammation.…”