• BMB Reports
• /
• v.53 no.9
• /
• pp.472-477
• /
• 2020

Osteoclasts are hematopoietic-derived cells that resorb bone. They are required to maintain proper bone homeostasis and skeletal strength. Although osteoclast differentiation depends on receptor activator of NF-κB ligand (RANKL) stimulation, additional molecules further contribute to osteoclast maturation. Here, we demonstrate that protocadherin-7 (Pcdh7) regulates formation of multinucleated osteoclasts and contributes to maintenance of bone homeostasis. We found that Pcdh7 expression is induced by RANKL stimulation, and that RNAi-mediated knockdown of Pcdh7 resulted in impaired formation of osteoclasts. We generated Pcdh7-deficient mice and found increased bone mass due to decreased bone resorption but without any defect in bone formation. Using an in vitro culture system, it was revealed that formation of multinucleated osteoclasts is impaired in Pcdh7-deficient cultures, while no apparent defects were observed in differentiation and function of Pcdh7-deficient osteoblasts. Taken together, these results reveal an osteoclast cell-intrinsic role for Pcdh7 in maintaining bone homeostasis.

• Journal of Microbiology and Biotechnology
• /
• v.31 no.6
• /
• pp.765-774
• /
• 2021

Although research on the osteal signaling pathway has progressed, understanding of gut microbial-dependent signaling pathways for metabolic and immune bone homeostasis remains elusive. In recent years, the study of gut microbiota has shed light on our understanding of bone homeostasis. Here, we review microbiota-mediated gut-bone crosstalk via bone morphogenetic protein/SMADs, Wnt and OPG/receptor activator of nuclear factor-kappa B ligand signaling pathways in direct (translocation) and indirect (metabolite) manners. The mechanisms underlying gut microbiota involvement in these signaling pathways are relevant in immune responses, secretion of hormones, fate of osteoblasts and osteoclasts and absorption of calcium. Collectively, we propose a signaling network for maintaining a dynamic homeostasis between the skeletal system and the gut ecosystem. Additionally, the role of gut microbial improvement by dietary intervention in osteal signaling pathways has also been elucidated. This review provides unique resources from the gut microbial perspective for the discovery of new strategies for further improving treatment of bone diseases by increasing the abundance of targeted gut microbiota.

• BMB Reports
• /
• v.46 no.10
• /
• pp.479-483
• /
• 2013

The balance between osteoblast-dependent bone formation and osteoclast-dependent bone resorption maintains bone homeostasis. In inflammatory conditions, this balance shifts toward bone resorption, causing osteolytic bone lesions observed in rheumatoid arthritis and periodontitis. A recently discovered family of cytokine IL-17 is widely reported to mediate diverse inflammatory processes. During the last decade, novel roles for IL-17 in skeletal homeostasis have been discovered indicating the potential importance of this cytokine in bone metabolism. This review will summarize and discuss the involvement of IL-17 during bone homeostasis in both physiologic and pathologic conditions. A better understanding of the role of IL-17 in skeletal systems warrants an advance in bone biology, as well as development of therapeutic strategies against bone-lytic diseases, such as rheumatoid arthritis and periodontitis.

• Molecules and Cells
• /
• v.37 no.8
• /
• pp.628-635
• /
• 2014

2-(Trimethylammonium) ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate [(R)-TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient megakaryopoiesis. Here, we show that (R)-TEMOSPho blocks osteoclast maturation from progenitor cells of hematopoietic origin, as well as blocking the resorptive function of mature osteoclasts. The inhibitory effect of (R)-TEMOSPho on osteoclasts was due to a disruption of the actin cytoskeleton, resulting from impaired downstream signaling of c-Fms, a receptor for macrophage-colony stimulating factor linked to c-Cbl, phosphoinositol-3-kinase (PI3K), Vav3, and Rac1. In addition, (R)-TEMOSPho blocked inflammation-induced bone destruction by reducing the numbers of osteoclasts produced in mice. Thus, (R)-TEMOSPho may represent a promising new class of antiresorptive drugs for the treatment of bone loss associated with increased osteoclast maturation and activity.

• Journal of Marine Bioscience and Biotechnology
• /
• v.15 no.1
• /
• pp.24-32
• /
• 2023

The Laminaria japonica Aresch (Sea tangle) belongs to the brown algae and has a long history as a food material in Asia, including Korea. Recent studies have found that the fermented Sea tangle extract (FST) inhibited the differentiation of osteoclasts and protected osteoblasts from oxidative damage. This study aims to explore the possibility that FST can induce the differentiation of osteoblasts and identify the responsible mechanism. According to our results, FST induced differentiation into osteogenic cells in the presence of osteoblastic MC3T3-E1 cells under non-toxic conditions.. This finding was confirmed by phalloidin staining, increased alkaline phosphatase activity, and calcium deposition. Additionally, it was found that this process was achieved by increasing the expression of key factors involved in osteoblast differentiation, such as runt-related transcription factor-2, osterix, β-catenin, and bone morphogenetic protein-2. Moreover, FST increased autophagy, which may contribute to the maintenance of the bone formation homeostasis, and is associated with the activation of the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase signaling pathways. Although further research about the bioactive substances contained in FST and the tests of their efficacy are required, the results of this study indicate that FST has incredible applicability as a functional material for maintaining the bone homeostasis.

• Asian-Australasian Journal of Animal Sciences
• /
• v.5 no.2
• /
• pp.303-308
• /
• 1992

Three female sheep were daily administered a pyrophosphate analogue, disodium 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) at the level of 4 mg/kg body weight. HEBP largely suppressed bone resorption, which was indicated by the reduction in plasma free hydroxyproline concentration and in calcium mobilization rate during the intravenous infusion of disodium ethylenediaminetetraacetate (EDTA). Contrary to the suppression of bone resorption, plasma total-calcium, magnesium and phosphorus concentrations were not changed by HEBP administration. These results suggest that bone mineral crystals play a meaningless role on calcium, magnesium and phosphorus homeostasis in ruminants if they are fed adequate amounts of these minerals. Plasma magnesium and phosphorus concentrations were not significantly changed after feeding. However, plasma total-calcium was decreased after feeding in both periods and the reduction seemed to be remarkable in the HEBP-treated period. Infusion of EDTA more remarkably reduced plasma ionized calcium concentration in the HEBP-treated that in the untreated period and the recovery of ionized calcium was retarded by HEBP administration. These results suggest that calcium release from bone is necessary for maintenance of plasma calcium when animals rapidly lose calcium.

• Journal of Microbiology and Biotechnology
• /
• v.33 no.9
• /
• pp.1197-1205
• /
• 2023

Osteoporosis, Greek for "porous bone," is a bone disease characterized by a decrease in bone strength, microarchitectural changes in the bone tissues, and an increased risk of fracture. An imbalance of bone resorption and bone formation may lead to chronic metabolic diseases such as osteoporosis. Wolfiporia extensa, known as "Bokryung" in Korea, is a fungus belonging to the family Polyporaceae and has been used as a therapeutic food against various diseases. Medicinal mushrooms, mycelium and fungi, possess approximately 130 medicinal functions, including antitumor, immunomodulating, antibacterial, hepatoprotective, and antidiabetic effects, and are therefore used to improve human health. In this study, we used osteoclast and osteoblast cell cultures treated with Wolfiporia extensa mycelium water extract (WEMWE) and investigated the effect of the fungus on bone homeostasis. Subsequently, we assessed its capacity to modulate both osteoblast and osteoclast differentiation by performing osteogenic and anti-osteoclastogenic activity assays. We observed that WEMWE increased BMP-2-stimulated osteogenesis by inducing Smad-Runx2 signal pathway axis. In addition, we found that WEMWE decreased RANKL-induced osteoclastogenesis by blocking c-Fos/NFATc1 via the inhibition of ERK and JNK phosphorylation. Our results show that WEMWE can prevent and treat bone metabolic diseases, including osteoporosis, by a biphasic activity that sustains bone homeostasis. Therefore, we suggest that WEMWE can be used as a preventive and therapeutic drug.

• Molecules and Cells
• /
• v.37 no.10
• /
• pp.747-752
• /
• 2014

Protein kinase C (PKC) family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. However, the role of PKC in receptor activator of NF-${\kappa}B$ ligand (RANKL) signaling has remained elusive. We now demonstrate that $PKC{\beta}$ acts as a positive regulator which inactivates glycogen synthase kinase-$3{\beta}$ (GSK-$3{\beta}$) and promotes NFATc1 induction during RANKL-induced osteoclastogenesis. Among PKCs, $PKC{\beta}$ expression is increased by RANKL. Pharmacological inhibition of $PKC{\beta}$ decreased the formation of osteoclasts which was caused by the inhibition of NFATc1 induction. Importantly, the phosphorylation of GSK-$3{\beta}$ was decreased by $PKC{\beta}$ inhibition. Likewise, down-regulation of $PKC{\beta}$ by RNA interference suppressed osteoclast differentiation, NFATc1 induction, and GSK-$3{\beta}$ phosphorylation. The administration of PKC inhibitor to the RANKL-injected mouse calvaria efficiently protected RANKL-induced bone destruction. Thus, the $PKC{\beta}$ pathway, leading to GSK-$3{\beta}$ inactivation and NFATc1 induction, has a key role in the differentiation of osteoclasts. Our results also provide a further rationale for $PKC{\beta}$'s therapeutic targeting to treat inflammation-related bone diseases.

• Journal of Rheumatic Diseases
• /
• v.24 no.1
• /
• pp.14-20
• /
• 2017

Interleukin-32 (IL-32), a recently identified pro-inflammatory cytokine, is involved in the pathogenesis and progression of infections, cancer, chronic inflammation, and autoimmune disease. IL-32γ is the most active isoform in cell death and cell activation among nine distinct isoforms of IL-32. IL-32γ potentiates both osteogenic and osteoclastogenic capacities, and is critical in the coupling of bone resorption and bone formation for maintenance of bone homeostasis. IL-32γ is strongly associated with inflammatory bone disorders such as rheumatoid arthritis, ankylosing spondylitis, and osteoporosis. In this review, we summarize current research on the role of IL-32γ in inflammatory bone disorders, highlighting this cytokine as a novel target for prognostic marker and control of these diseases.

• Journal of Marine Bioscience and Biotechnology
• /
• v.5 no.4
• /
• pp.1-7
• /
• 2011

Bone health is maintained by balance between bone resorption and bone formation, and bone homeostasis requires balanced interactions between osteoblasts and osteoclasts. Most of drugs and functional foods for bone health have been developed as bone resorption inhibitors, which maintain bone mass by inhibiting the function of osteoclasts. The recent studies have shown beneficial effects of marine natural products on bone health. Therefore, this review is aimed to study effects of marine-derived natural substances on osteoarthritis inhibition via attenuation of MMPs and osteoblastic differentiation via activation of alkaline phosphatase (ALP), osteoclacin (OC), bone morphogenic protein-2 (BMP-2) as an important factor for bone formation, and mineralization. The present review can provide new insights in the osteoblastic differentiation of marine natural products and possibility for their application in bone health supplement.