From Osteoclast Differentiation to Osteonecrosis of the Jaw: Molecular and Clinical Insights

Abstract

Bone physiology relies on the delicate balance between resorption and formation of its tissue. Bone resorption depends on a process called osteoclastogenesis in which bone-resorbing cells, i.e., osteoclasts, are produced by the differentiation of more undifferentiated progenitors and precursors. This process is governed by two main factors, monocyte-colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). While the former exerts a proliferating effect on progenitors/precursors, the latter triggers a differentiation effect on more mature cells of the same lineage. Bone homeostasis requires a perfect space–time coordination of the involved signals. When osteoclastogenesis is poorly balanced with the differentiation of the bone forming counterparts, i.e., osteoblasts, physiological bone remodelling can turn into a pathological state, causing the systematic disruption of bone tissue which results in osteopenia or osteolysis. Examples of these conditions are represented by osteoporosis, Paget’s disease, bone metastasis, and multiple myeloma. Therefore, drugs targeting osteoclastogenesis, such as bisphosphonates and an anti-RANKL monoclonal antibody, have been developed and are currently used in the treatment of such diseases. Despite their demonstrated therapeutic efficacy, these agents are unfortunately not devoid of side effects. In this regard, a condition called osteonecrosis of the jaw (ONJ) has been recently correlated with anti-resorptive therapy. In this review we will address the involvement of osteoclasts and osteoclast-related factors in the pathogenesis of ONJ. It is to be hoped that a better understanding of the biological mechanisms underlying bone remodelling will help in the design a medical therapeutic approach for ONJ as an alternative to surgical procedures.

Corilagin suppresses RANKL‐induced osteoclastogenesis and inhibits oestrogen deficiency‐induced bone loss via the NF‐κB and PI3K/AKT signalling pathways

“…After binding of RANKL to RANK, TRAF6 is activated and forms a complex with TAK1 47 . Activated TAK1 subsequently phosphorylates the IKK/IκBα and MAPK pathways, leading to activation of the NF‐κB pathway and activated protein 1 (AP‐1) 17,18,48 . Our results showed that Corilagin suppressed the phosphorylation of NF‐κB but did not affect that of p38, ERK or JNK.…”

The Administration of 4-Hexylresorcinol Accelerates Orthodontic Tooth Movement and Increases the Expression Level of Bone Turnover Markers in Ovariectomized Rats

“…As bone deposition is required on the tension side during orthodontic tooth movement, an increased expression of BMP-2 at this site may be attributed to its role in active bone formation. RANKL is a marker for osteoclasts [29]. The expression of RANKL was mainly observed on the compression side, as opposed to the tension side ( Figure 6), indicating its role in active bone resorption.…”

“…Thereafter, the expression levels of these proteins decreased to the level of the non-treated control at 16 and 24 h (Figure 4). At 16 h, 4HR induced overexpression of RANKL (osteoclast differentiation factor) [29], RUNX2 (a key transcription factor associated with osteoblast differentiation) [30], osterix (a transcription factor for osteoblast differentiation) [31], aggrecan (a cartilage-specific proteoglycan core protein) [32], and calmodulin-dependent kinase II (a key regulator of osteoblast differentiation) [33], which co-operatively stimulated osteoblast differentiation. At 24 h, 4HR induced overexpression of BMP-3 (a negative regulator for bone density) [34], OPG (a regulator for bone density) [35], osteocalcin (a calcium-binding protein) [36], and osteopontin (bone sialoprotein I) [37], which simultaneously regulated osteoid matrix deposition.…”

Crizotinib-induced osteitis mimicking bone metastasis in a stage IV ALK-rearranged NSCLC patient: a case report

“…PDGF signalling might have been involved in our patient's osteitis. Other drug-induced osteonecrosis mechanisms are known such as Cyclooxygenoase 2 inhibition by non-steroid anti-inflammatory drugs and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) inhibition by bisphosphonates [18]. Crizotinib as no direct interaction with these pathways.…”