• BMB Reports
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• 제52권9호
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• pp.572-576
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• 2019

Bisphosphonates are the mainstay of therapy worldwide for osteoporosis. However, bisphosphonates also have limitations. The objective of this study was to determine the role of miR-101-3p/Rap1b signal pathway in osteoclast differentiation after treatment with bisphosphonates. Our results revealed that miR-101-3p was an important regulator in bisphosphonates treated-osteoclasts. When miR-101-3p was down-regulated in bone marrow-derived macrophage-like cells (BMMs), the development of mature osteoclasts was promoted, and vice versa. However, alendronate decreased multinucleated cell number regardless of whether miR-101-3p was knocked down or over-expressed. TRAP activity assay confirmed the above results. Luciferase assay indicated that miR-101-3p was a negative regulator of Rap1b. Western blot analysis revealed that protein expression level of Rap1b in BMMs transfected with OV-miR-101-3p was lower than that in BMMs transfected with an empty vector. Rap1b overexpression increased TRAP-positive multinucleated cells, while Rap1b inhibition decreased the cell numbers. In vivo data showed that miR-101-3p inhibited osteoclast differentiation in ovariectomized mice while overexpressed of Rap1b blocked the differentiation. Taken together, our data demonstrate that miR-101-3p/Rap1b signal pathway plays a key role in osteoclast differentiation after treatment with bisphosphonates.

• Imaging Science in Dentistry
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• 제51권1호
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• pp.73-80
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• 2021

Purpose: The purpose of this study was to evaluate the cone-beam computed tomographic (CBCT) imaging and histopathological characteristics of osteoradionecrosis(ORN) and medication-related osteonecrosis of the jaw(MRONJ). Materials and Methods: Ten surgical specimens from segmental mandibulectomy (3 ORN and 7 MRONJ) were analyzed using CBCT. The CBCT parameters were as follows: high-resolution mode (tube voltage, 90.0 kV; tube current, 4.00 mA; rotation time, 16.8 s; field of view, 56 mm×56 mm; thickness, 0.099 mm). Histopathological characteristics were evaluated using histological slides of the surgical specimens. The Pearson chi-square test was used to compare ORN and MRONJ in terms of CBCT findings(internal texture, sequestrum, periosteal reaction and cortical perforation) and histopathological characteristics(necrotic bone, inflammatory cells, reactive bone formation, bacteria, Actinomyces, and osteoclasts). A P value less than 0.05 was considered to indicate statistical significance. Results: MRONJ showed periosteal reaction on CBCT more frequently than ORN (7 of 7 [100%] vs. 0 of 3 [0%], P<0.05). Regarding histopathological characteristics, MRONJ showed osteoclasts more frequently than ORN (6 of 7 [85.7%] vs. 0 of 3 [0%], P<0.05). Conclusion: This study evaluated the CBCT imaging and histopathological characteristics of ORN and MRONJ, and the findings suggest that CBCT could be useful for the evaluation of ORN and MRONJ.

• 생약학회지
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• 제53권1호
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• pp.42-48
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• 2022

In order to maintain bone homeostasis, it is necessary to balance bone resorption and remodeling through the differentiation of osteoclasts that absorb old bone and osteoblasts that form new bone. However, bone resorption due to excessive osteoclast differentiation is a major cause of osteoporosis and controlling excessive osteoclast differentiation has been known as a treatment strategy for osteoporosis. Therefore, in this study, the effect of an ethanol extract of Sphaerotylus antarcticus Kirkpatrick, 1907 (SAE), polar-derived sponge with unknown biological activity, on the osteoclast differentiation process of RANKL-induced RAW264.7 cells and the generated ROS was evaluated. In the study results, SAE down-regulated the formation and function of RANKL-induced osteoclasts and osteoclast differentiation specific proteins, genes in a concentration-dependent manner. In addition, it was possible to confirm the result of restoring the lost antioxidant enzyme along with down-regulation of ROS generated by RANKL. Therefore, in this study, we propose the possibility of SAE as a potential regulator of osteoporosis due to excessive osteoclast differentiation and report the biological value of the diversity of marine-derived natural products by identifying the first biological activity against SAE that is not yet known.

• 치위생과학회지
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• 제6권1호
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• pp.1-9
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• 2006

기계적 자극에 의한 골조직의 개조에서 압박측은 일차적으로 파골세포에 의하여 골기질의 흡수를 위한 유전자 발현에 의하여 기시된다. 그러나 기질을 이루는 유기 단백질의 흡수에 관여하는 단백용해효소의 세포 내 작용 기전은 여전히 완전히 이해되지 않고 있다. 이 연구는 파골세포에서 용해용소체효소인 cathepsin k에 주목하여, cAMP 길항제와 PKA 억제제 및 adenylate cyclase 촉진제에 의한 cathepsin k 생성의 촉진 또는 억제 효과의 기전을 해명하는데 그 목적을 두었다. cAMP 길항제인 Rp-cAMP와 PKA 억제제인 KT5720과 H89는 cathepsin K의 세포 내성숙을 차단하였으며, 대조적으로 adenylate cyclase 촉진제 forskolin은 파골세포에서의 cathepsin K의 생성과 성숙을 유인하는 것으로 나타났다. 특히 cathepsin K의 생성과 성숙에 관여하는 신호전달이 protein kinase C(PKC)와 관련성을 검정하기 위하여 백서의 골세포를 PKC의 선택적 억제제인 calphostin C로 처리하였을 때 아무런 영향이 없는 것으로 나타남으로써 calphostin C는 파골 세포에 의해 매개된 cathepsin K의 생성과 성숙과는 무관한 것으로 밝혀졌다. 이는 파골세포에서의 cathepsin K의 성숙은 cAmp-PKA 신호전달 경로에 의해 조절됨을 의미한다. 분비된 전구효소는 M6P 수용체를 통하여 세포 내로 다시 진입할 수 있는 잠재성을 가지고 있기 때문에 이러한 가능성을 차단하기 위하여 M6P가 존재 또는 결여된 상태에서 cAMP 길항제인 Rp-cAMP와 PKA 억제제인 KT5720 및 H89를 시험하였다. 그 결과 Rp-cAMP, KT5720 또는 H89에 의한 cathepsin K의 M6P용량 비례적 생성 억제가 관찰 되었다. 또한 M6P를 주었을 때 Rp-cAMP, KT5720와 H89의 작용이 증가된을 보였다. 이상에서와 같이 Rp-cAMP, KT5720와 H89의 cathepsin K 생성 방해를 통한 골흡수 억제는 골다공증 또는 관절염의 치료와 같은 골흡수의 억제를 필요로 하는 분야에서의 임상적응용 가능성을 시사한다.

• 치과방사선
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• 제8권1호
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• pp.11-15
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• 1978

The author observed the effect of x-ray irradiation on the development of the mandible in the fetuses and growing albino rats. The fetuses were irradiated on the 7½th day of gestation, 100, 200, 300, and 400 rads of x-ray respectively. The experimental animals were sacrificed on the 18½th day of gestation, and first week, second week and third week after parturition. The results were as follows; 1. The mandible of the 18½th day fetuses showed irregular bone trabeoulae, osteoclasts and osteocyte degeneration on the 300 and 400 rads x-ray irradiated fetuses. 2. In the mandible of the first week rats, there was marked osteocyte degeneration and a lot of osteoclast. 3. In the mandible of the 2nd and 3rd week rats bone remodeling was evident. The 3rd week rats also showed alteration of blood vessel wall.

• 대한의생명과학회지
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• 제23권4호
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• pp.295-302
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• 2017

Mononuclear osteoclast precursors derived from hematopoietic progenitors fuse together and then become multinucleated mature osteoclasts by macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL). Especially, the binding of RANKL to its receptor RANK provides key signals for osteoclast differentiation and bone-resorbing function. RANK transduces intracellular signals by recruiting adaptor molecules such as TNFR-associated factors (TRAFs), which then activate mitogen activated protein kinases (MAPKs), Src/PI3K/Akt pathway, nuclear factor-${\kappa}B$ (NF-${\kappa}B$) and finally amplify NFATc1 activation for the transcription and activation of osteoclast marker genes. This review will briefly describe RANKL-RANK signaling pathways and key molecules critical for osteoclast differentiation.

• 약학회지
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• 제52권1호
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• pp.43-47
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• 2008

To determine the regulatory roles of PDE4 inhibitor on LPS-induced osteoclastogenesis, we investigated the effect of a PDE4 inhibitor on osteoclast formation in the presence of LPS. A specific PDE4 inhibitor, rolipram, increased LPS-induced osteoclast formation in cocultures. To verify that whether rolipram acts indirectly on osteoblasts, we investigated the TRANCE and COX-2 mRNA expression levels in osteoblasts. Treatment of rolipram increased the expression of TRANCE and COX-2 mRNA in osteoblasts stimulated by LPS. On the contrary, rolipram did not augment the number of osteoclasts differentiated from bone marrow cells by LPS. In conclusion, the stimulation of LPS-induced osteoclast formation by the PDE4 inhibitor are attributable to its indirect effect on osteoblasts, not to their direct effect on bone marrow-derived osteoclast precursors.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제33권4호
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• pp.381-385
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• 2007

Bone is a dynamic organ that bone remodeling occurs throughout life and involves the process in which the bone matrix is broken down through resorption by osteoclasts and then built back again through bone formation by osteoblasts. Usually these two processes balance each other and a stable level of bone mass is maintained. We here discuss transcription factors involved in regulating the osteoblast differentiation pathway. Runx2 is a transcription factor which is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation. Its companion subunit, Cbf${\beta}$ is needed for an early step in osteoblast differentiation pathway. Whereas Osterix(Osx) is a new identified osteoblast-specific transcription factor which is required for the differentiation of preosteoblasts into more mature and functional osteoblasts. We also discuss other transcription factors, Msx1 and 2, Dlx5 and 6, Twist, and Sp3 that affect skeletal patterning and development. Understanding the characteristics of mice in which these transcription factors are inactivated should help define their role in bone physiology and pathology of bone defects.

• Molecules and Cells
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• 제40권11호
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• pp.880-887
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• 2017

We hypothesized that inflammation affects number and activity of osteoclasts (OCs) via enhancing autophagy. Lipopolysaccharide (LPS) induced autophagy, osteoclastogenesis, and cytoplasmic reactive oxygen species (ROS) in bone marrow-derived macrophages that were pre-stimulated with receptor activator of nuclear $factor-{\kappa}B$ ligand. An autophagy inhibitor, 3-methyladenine (3-MA) decreased LPS-induced OC formation and bone resorption, indicating that autophagy is responsible for increasing number and activity of OCs upon LPS stimulus. Knockdown of autophagy-related protein 7 attenuated the effect of LPS on OC-specific genes, supporting a role of LPS as an autophagy inducer in OC. Removal of ROS decreased LPS-induced OC formation as well as autophagy. However, 3-MA did not affect LPS-induced ROS levels, suggesting that ROS act upstream of phosphatidylinositol-4,5-bisphosphate 3-kinase in LPS-induced autophagy. Our results suggest the possible use of autophagy inhibitors targeting OCs to reduce inflammatory bone loss.

• Biomolecules & Therapeutics
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• 제19권2호
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• pp.141-148
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• 2011

Osteoclasts are bone-resorbing cells of monocyte/macrophage origin and are culprits of bone destruction associated with osteoporosis, rheumatoid arthritis, and cancer bone metastasis. Recent advances in osteoclast biology revealed central roles of various cytokines in regulating osteoclastogenesis both in vitro and in vivo. However, exact underlying mechanisms including signaling pathways downstream of receptor ligation are still under pursuit. In the present review, the role of Jak/STAT proteins and their regulators will be discussed in connection with osteoclastogenesis, since growing evidence indicates that a number of cytokines and growth factors utilizing Jak/STAT signaling pathways affect osteoclastogenesis. A better understanding on the role of Jak/STAT pathways in osteoclast differentiation will not only strengthen our knowledge on osteoclast biology but also provide invaluable insights into the development of anti-resorptive strategies for treating bone-lytic diseases.