Osteoclastogenesis Inhibitory Factor (OCIF) Directly Inhibits Bone-Resorbing Activity of Isolated Mature Osteoclasts

doi:10.1006/bbrc.1998.9523

Biochemical and Biophysical Research Communications

Volume 251, Issue 3, 29 October 1998, Pages 796-801

https://doi.org/10.1006/bbrc.1998.9523 Get rights and content

Abstract

Osteoclastogenesis inhibitory factor (OCIF) was previously reported to specifically inhibit osteoclast development by interrupting the action of osteoclast differentiation factor (ODF), which is expressed in stromal cells and plays an important role in osteoclastogenesis. Here we report the direct action of OCIF on isolated rabbit mature osteoclasts to inhibit their functional bone-resorbing activity. The cell population employed in this study consisted of mature osteoclasts with more than 95% of purity. The inhibition by OCIF was dose dependent and observed as early as 6 h after the OCIF addition. An OCIF-binding protein of 140 kDa was detected on the plasma membrane of osteoclasts. ODF with aMrof 40 kDa was recently isolated as a ligand for OCIF and shows to be identical to TRANCE/RANKL. However, ODF was not detected in osteoclasts. OCIF did not have any impact on the mRNA levels of cathepsin K/OC2 and carbonic anhydrase II responsible for degradation of organic and inorganic bone matrices, respectively, or on osteoclast apoptosis. However, OCIF reduced or disrupted the formation of F-actin ring in isolated osteoclasts, the cytoskeletal structure of which is correlated with bone resorption. These findings demonstrate that OCIF directly inhibits osteoclast function through an ODF-independent mechanism besides blocking the generation of osteoclasts.

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In order to develop a better therapeutic approach for the treatment of rheumatoid arthritis (RA), withaferin-A; a steroidal lactone incorporated with mannosylated liposomes (ML-WA) was administered to adjuvant induced arthritic rats in intent to target the synovial macrophages. The confocal microscopy studies showed a successful internalization of ML-WA in the primarily isolated synovial macrophages. Consequently, targeting synovial macrophages via ML-WA reduced the oxidative stress (ROS and NO), and paw edema, however, a progressive gain in the body weight was observed in AIA rats. ML-WA treatment upregulated the production of osteoprotegerin (OPG) and downregulated the release of receptor activator of nuclear factor-κB ligand (RANKL), favoring osteoclastogenesis negatively. Correspondingly, the ankle joints were found intact with no bone erosion and cartilage degradation in ML-WA treated AIA rats as evidenced by histopathological analysis. Also, synovial macrophage assessment showed that the concentration and the gene amplification of M1 macrophage mediated pro-inflammatory mediators (TNF-α, IL-1β, IL-6, MCP-1 and VEGF) were curtailed in ML-WA treated AIA rats. In contrast, anti-inflammatory cytokine (IL-10) was found abundantly released. Furthermore, the mRNA expression of the M1 surface marker (CD86) was found down regulated, whereas, M2 marker (CD163) was highly amplified in ML-WA treated synovial macrophages of arthritic rats. Cumulatively, our result signified that targeted delivery of ML-WA ameliorated the severity of inflammation and bone resorption in AIA rats via M1 to M2 macrophage repolarization.
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It therefore inhibits the catabolic effects of RANKL. Formation, attachment to the bone [22,23], activation [3–5] and survival [24,25] of osteoclasts are effectively stopped. The cortical and cancellous bone volume, density and strength are increased.
The discovery of the OPG/RANK/RANKL pathway two decades ago has initiated novel insights into regulation of bone formation. More recently this pathway has been found to be also relevant in osteoclastic-independent mechanisms, mainly in mammary physiology and breast cancer. RANKL/RANK function is essential for epithelial cell proliferation and cellular survival as well as lobulo-alveolar development. The endogenous OPG functions as a soluble decoy receptor, binding the cytokine RANKL to prevent RANKL from activating its receptor RANK. The regulatory function of RANKL is one of the key factors in progesterone-induced proliferation of the breast. Progesterone has a direct action of progesterone on progesterone-receptor (PR) expressing cells but PR-negative cells are affected indirectly through RANKL-induced paracrine actions leading to proliferation of mammary epithelial PR-negative cells. RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Inhibition of the RANK/RANKL pathway using the monoclonal antibody denosumab can neutralize RANKL and inhibiting its interaction with its receptor RANK. Denosumab is currently used to treat osteoporosis and in prevention of skeletal related events in patients suffering from bone metastases due to solid tumors. As preclinical experiments suggest the RANKL/RANK pathway plays an important role in primary breast cancer development. The interference with the RANK/RANKL system could therefore serve as a potential target for prevention and treatment of breast cancer.
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However, the interaction between RANKL and RANK receptor can be blocked by OPG, a secreted glycoprotein which produced and released by osteoblast [19]. OPG competitively binds to RANKL and prevents RANKL from binding and activating RANK, which leads to prevention of osteoclastogenesis, increases apoptosis of mature osteoclasts, inhibits activation of existing osteoclasts and decreases osteoclast number [20–22]. To understand the process of bone formation and remodel between implant materials and bone tissues in detail, it is necessary to assess the effects in the interactions of osteoblasts with implant materials.
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Osteoprotegerin, however, is not directly related to osteoclasts, acting as a decoy receptor of RANKL, inhibiting osteoclast formation, but reports of immunohistochemical staining to OPG in osteoclasts have already been described.14 Hakeda et al. 22 have detected an OPG-binding protein of 140 kDa on the plasma membrane of isolated rabbit mature osteoclasts. Binding of OPG to this protein reduced or disrupted the formation of F-actin ring in isolated osteoclasts, the cytoskeletal structure of which is correlated with bone resorption.
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OPG is a decoy receptor for RANKL and down-regulates the RANKL signaling through RANK. OPG acts as an antagonist receptor that neutralizes the biological effects of RANKL and thus represents a bone resorption inhibitor [35]. In this study, we found that OPG expression was significantly increased after OVX, which was in accordance with the results of Ikeda et al. [36], while there was no significant difference in the expression of OPG following the treatment.
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In order to investigate the underlying mechanism of alterations in bone mineral metabolism in patients with type 2 diabetes, we determined circulating levels of bone functional markers along with urinary excretion of sorbitol (SOR) and bone mineral density (BMD), and also examined their mutual interrelationship. A total of 151 male type 2 diabetic patients were examined in this study. Forty-eight age-matched male healthy subjects were also studied as the controls. A significant reduction of serum intact osteocalcin (i-OC) was found in the diabetic groups (p < 0.01). On the other hand, circulating levels of tartrate resistant acid phosphatase (TRAP) in the diabetic patients were significantly higher than those in the controls (p < 0.01). Interestingly, a significantly negative relationship was observed between BMD and serum TRAP (p < 0.01), although no significant relationship was noted between BMD and serum i-OC in diabetic patients. Urinary excretion of SOR was significantly elevated in the diabetic patients when compared with the controls (p < 0.01). In addition, a significantly positive correlation was observed between serum TRAP and urinary SOR (p < 0.01), but not between serum i-OC and urinary SOR. Elevated serum TRAP in diabetes was reduced after the administration of aldose reductase inhibitor (p < 0.05). It seems most likely that the increase in osteoclastic function probably due to accelerated polyol pathway plays a crucial role in the pathogenesis of decreased bone mineral content in male patients with type 2 diabetes.

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^☆: Bilezikian, J. P.Raisz, L. G.Rodan, G. A.

¹: Corresponding author. Fax: +81-493-71-3523. E-mail:[email protected].

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Regular ArticleOsteoclastogenesis Inhibitory Factor (OCIF) Directly Inhibits Bone-Resorbing Activity of Isolated Mature Osteoclasts☆

Abstract

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

Cell

Biochem. Biophys. Res. Commun.

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Biochem. Biophys. Res. Commun.

Anal. Biochem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Exp. Cell. Res.

Principles of Bone Biology

Regular Article
Osteoclastogenesis Inhibitory Factor (OCIF) Directly Inhibits Bone-Resorbing Activity of Isolated Mature Osteoclasts☆