Macrophage Migration Inhibitory Factor (MIF) Supports Homing of Osteoclast Precursors to Peripheral Osteolytic Lesions

Abstract

By binding to its chemokine receptor CXCR4 on osteoclast precursor cells (OCPs), it is well known that stromal cell-derived factor-1 (SDF-1) promotes the chemotactic recruitment of circulating OCPs to the homeostatic bone remodeling site. However, the engagement of circulating OCPs in pathogenic bone resorption remains to be elucidated. The present study investigated a possible chemoattractant role of macrophage migration inhibitory factor (MIF), another ligand for C-X-C chemokine receptor type 4 (CXCR4), in the recruitment of circulating OCPs to the bone lytic lesion. To accomplish this, we used Csf1r-eGFP-knock-in (KI) mice to establish an animal model of polymethylmethacrylate (PMMA) particle-induced calvarial osteolysis. In the circulating Csf1r-eGFPþ cells of healthy Csf1r-eGFP-KI mice, Csf1rþ/CD11bþ cells showed a greater degree of RANKL-induced osteoclastogenesis compared to a subset of Csf1rþ/RANKþ cells in vitro. Therefore, Csf1r-eGFPþ/CD11bþ cells were targeted as functionally relevant OCPs in the present study. Although expression of the two cognate receptors for MIF, CXCR2 and CXCR4, was elevated on Csf1rþ/CD11bþ cells, transmigration of OCPs toward recombinant MIF in vitro was facilitated by ligation with CXCR4, but not CXCR2. Meanwhile, the level of PMMA-induced bone resorption in calvaria was markedly greater in wild-type (WT) mice compared to that detected in MIF-knockout (KO) mice. Interestingly, in contrast to the elevated MIF, diminished SDF-1 was detected in a particle-induced bone lytic lesion of WT mice in conjunction with an increased number of infiltrating CXCR4þ OCPs. However, such diminished SDF-1 was not found in the PMMA-injected calvaria of MIF-KO mice. Furthermore, stimulation of osteoblasts with MIF in vitro suppressed their production of SDF-1, suggesting that MIF can downmodulate SDF-1 production in bone tissue. Systemically administered anti-MIF neutralizing monoclonal antibody (mAb) inhibited the homing of CXCR4þ OCPs, as well as bone resorption, in the PMMA-injected calvaria, while increasing locally produced SDF-1. Collectively, these data suggest that locally produced MIF in the inflammatory bone lytic site is engaged in the chemoattraction of circulating CXCR4þ OCPs.

OC‐STAMP promotes osteoclast fusion for pathogenic bone resorption in periodontitis via up‐regulation of permissive fusogen CD9

“…However, because OC-STAMP-KO mice show no bone phenotype, the present study was predicated on the hypothesis that OC-STAMP must be engaged in pathogenic bone resorption in periodontitis. On the other hand, we reported that OCps in circulation are recruited to the wear debris-induced bone lytic lesion through a unique chemokine, macrophage migration inhibitory factor (MIF), locally produced in the lesion (23), as opposed to stromal-derived factor 1 (SDF-1), which chemoattracts OCps in circulation to the healthy bone remodeling site (49). This study revealed that migration of CXCR4 + OCps in the circulation to either normal bone remodeling or pathogenic bone resorption sites is controlled by 2 different chemokines, MIF or SDF-1, respectively, suggesting that MIF mediates the recruitment of OCps toward pathogenic bone resorption lesion, whereas SDF-1 is engaged in the recruitment of OCps to the healthy homeostatic bone remodeling site (23).…”

“…On the other hand, we reported that OCps in circulation are recruited to the wear debris-induced bone lytic lesion through a unique chemokine, macrophage migration inhibitory factor (MIF), locally produced in the lesion (23), as opposed to stromal-derived factor 1 (SDF-1), which chemoattracts OCps in circulation to the healthy bone remodeling site (49). This study revealed that migration of CXCR4 + OCps in the circulation to either normal bone remodeling or pathogenic bone resorption sites is controlled by 2 different chemokines, MIF or SDF-1, respectively, suggesting that MIF mediates the recruitment of OCps toward pathogenic bone resorption lesion, whereas SDF-1 is engaged in the recruitment of OCps to the healthy homeostatic bone remodeling site (23). To our knowledge, OC-STAMP appears to be the OC fusionregulatory molecule that is distinctively engaged in pathogenic bone resorption in periodontitis but not in homeostatic bone remodeling, which stands in contrast to DC-STAMP, which is engaged in both homeostatic and pathogenic bone remodeling by increasing cell fusion in a manner independent of OC-STAMP/CD9.…”

“…We have recently developed an anti-DC-STAMP-mAb (mouse IgG2a) that can neutralize the cell fusion event in RANKLinduced OCs (12). Anti-OC-STAMP-mAb (mouse IgG3) was generated by the methods previously reported (21)(22)(23). Briefly, 8 wk old BALB/c mice were immunized with highly specific peptide sequences of mouse OC-STAMP protein (OC-STAMP peptide: FASMQRSFQWELRFTPHDCHLPQAQPPR), which were designed using a BLAST search.…”

TRAP-positive osteoclast precursors mediate ROS/NO-dependent bactericidal activity via TLR4

“…Especially it has become evident that OCps in the circulation migrate to intact bone as well as inflammatory bone resorption lesion and participate in bone resorption [57,58], suggesting that OCps function similar to innate immune macrophages [59]. For this reason, it is plausible that any pharmaceutical intervention for bone lytic diseases that targets osteoclast differentiation, such as bisphosphonate and Denosumab [60,61], would attenuate the OCps-mediated anti-bacterial barrier mechanism for alveolar bone.…”

Phosphoglycerol dihydroceramide, a distinctive ceramide produced by Porphyromonas gingivalis, promotes RANKL-induced osteoclastogenesis by acting on non-muscle myosin II-A (Myh9), an osteoclast cell fusion regulatory factor

“…To evaluate the effects of PGDHC on in vivo osteoclastogenesis, a mouse model of calvarial injection was utilized following a published protocol with some modifications [30]. Under anesthesia with ketamine (80 mg/kg) and xylazine (10 mg/kg), WT or TLR2/4 DKO mice (6- to 8-week-old; 5 mice/group) received a calvarial injection of the following solutions: 1) 0.1% ethanol in PBS (control); 2) 10 μg/ml of murine recombinant RANKL (rRANKL) dissolved in PBS containing 0.1% ethanol; 3) a mixture of 10 μg/ml of murine rRANKL and 10 μg/ml of PGDHC dissolved in PBS containing 0.1% ethanol.…”