The Mechanism of Osteoclast Differentiation Induced by IL-1

Abstract

IL-1 is a potent cytokine that can induce bone erosion in inflammatory sites such as rheumatoid joint regions via activation of osteoclasts. Not only is IL-1 capable of activating osteoclasts, but it is also a key cytokine involved in the differentiation, multinucleation, and survival of osteoclasts. Herein, we show that IL-1 has the potential to drive osteoclast differentiation via a receptor activator of NF-κB ligand (RANKL)/RANK-independent mechanism. Although IL-1 has a synergistic effect on RANKL-induced osteoclast formation, IL-1 alone cannot induce osteoclast differentiation from osteoclast precursors (bone marrow-derived macrophages (BMMs)) due to a lack of IL-1 signaling potential in these cells. However, we demonstrate that overexpression of the IL-1RI receptor in BMMs or induction of IL-1RI by c-Fos overexpression enables IL-1 alone to induce the formation of authentic osteoclasts by a RANKL/RANK-independent mechanism. The expression of IL-1RI is up-regulated by RANKL via c-Fos and NFATc1. Furthermore, the addition of IL-1 to IL-1RI overexpressing BMMs (IL-1/IL-1RI) strongly activates NF-κB, JNK, p38, and ERK which is a hallmark gene activation profile of osteoclastogenesis. Interestingly, IL-1/IL-1RI does not induce expression of c-Fos or NFATc1 during osteoclast differentiation, although basal levels of c-Fos and NFATc1 seem to be required. Rather, IL-1/IL-1RI strongly activates MITF, which subsequently induces osteoclast-specific genes such as osteoclast-associated receptor and tartrate-resistant acid phosphatase. Together, these results reveal that IL-1 has the potential to induce osteoclast differentiation via activation of microphthalmia transcription factor under specific microenvironmental conditions.

Molecular Understanding of Osteoclast Differentiation and Physiology

“…Recently, it has been found that NFATc1 functions in the osteoclast fusion process via up-regulation of the dendritic cell-specific transmembrane protein (DC-STAMP) and the d2 isoform of vacuolar ATPase V0 domain (Atp6v0d2) through co-activation with MEF2 and MITF, which would be followed [58,59]. Moreover, interleukin-1 (IL-1) activates osteoclast-specific genes including TRAP and OSCAR, in part, via the MITF pathway [61]. Mi mutant osteoclasts are primarily mononuclear and express decreased levels of TRAP [41,62].…”

Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures

“…10,19,20 This is particularly relevant in relation to post-menopausal bone loss, where estrogen depletion results in increased production and release of IL-1, and subsequently osteoclast formation and bone resorption. 21 It has been demonstrated that P2X7 is involved in mechanically induced signalling between osteoblasts and osteoclasts, 14 as well as with osteoclast survival. 12,17,22 Furthermore, it has been shown to couple to NF-kB in osteoclasts.…”

WHI-131 Promotes Osteoblast Differentiation and Prevents Osteoclast Formation and Resorption in Mice

“…A previous report demonstrated that overexpression of IL-1 in bone marrow macrophages (BMMs) resulted in the activation of NF-kB, JNK, p38, and the extracellular signal-regulated kinases (ERK) pathway, which is a hallmark of osteoclast differentiation, and also enhanced microphthalmia-associated transcription factor activity, thereby inducing the expression of osteoclast marker genes such as osteoclast-associated receptor (OSCAR) and tartrate-resistant acid phosphatase (TRAP). (10) Therefore, the actions of these proinflammatory cytokines affect the balance between bone mineralization and resorption regulated by the opposing actions of osteoblasts and osteoclasts.…”