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Identification of Alternatively Spliced Forms of human OSCAR in Osteoclasts
김낙성,박홍용,김현동 대한골대사학회 2012 대한골대사학회지 Vol.19 No.1
Objectives: Osteoclasts are multinucleated giant cells which can resorb bone and differentiated from hematopoietic cells. We have previously reported murine osteoclast-associated receptor (OSCAR) may be an important bone-specific regulator of osteoclast differentiation. We have cloned soluble form of human OSCAR (hOSCAR) and examined the role of hOSCAR on osteoclast differentiation. Methods: Osteoclast differentiation was induced by treatment with macrophage colony-stimulating factor (M-CSF)and receptor activator of nuclear factor kappa B ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP)staining and pit formation were performed. Expression was measured by flow cytometry analysis, Northern and Western blot analysis. Results: hOSCAR is expressed in osteoclast cells and involved in the differentiation of osteoclasts from peripheral blood mononuclear cells (PBMC). Two alternatively spliced forms (soluble hOSCAR [hOSCAR-S]) of hOSCAR were identified from osteoclasts complementary deoxyribonucleic acid (cDNA) library derived from PBMC. Putative transmembrane domain was not found in hOSCAR-S forms and it suggested that these forms might be secreted from osteoclast cells. These secreted forms of hOSCAR attenuated RANKL-induced osteoclast formation and bone resorption. Conclusions: Human osteoclasts express at least five different OSCAR messenger ribonucleic acid (mRNA) isoforms which could play different regulatory roles for differentiation. The secreted forms of hOSCAR might be a negative regulator of membrane-bounded forms of OSCAR. 연구목적: 파골세포는 다핵 세포로서 골흡수를 유발한다. 생쥐에서 OSCAR는 파골세포 분화에서 중요한 역할을 함이 밝혀졌다. 인간 OSCAR의 분비형이 클로닝되었고 이들의 파골세포 분화에서의 역할을 분석하고자 하였다. 연구방법: 파골세포 분화는 M-CSF와 RANKL의 처리에 의해 유도하였으며 TRAP 염색법과 pit 형성도를 측정하였다. 발현 정도는 유세포분석, Northern, 및 Western 분석 방법을 사용하였다. 결 과: 인간 OSCAR는 파골세포에서 발현하였으며 PBMC로부터 유도되는 파골세포 형성에 관여하였다. 선택적 이어맞추기에 의해 만들어진 두 종류의 인간 OSCAR가 확인되었다. 이들은 막관통영역이 없는 구조로서 파골세포로부터분비되는 형태로 존재하였다. 이러한 분비형의 인간 OSCAR는 파골세포 분화 및 골흡수를 저해하였다. 결 론: 인간 OSCAR는 최소 5종류의 구조적아형을 갖고 있으며, 이들은 서로 다른 역할을 하고 있다. 특히 분비형인간 OSCAR는 파골세포 분화에서 음성 조절자로서 역할을 한다.
SLAT Negatively Regulates RANKL-Induced Osteoclast Differentiation
윤방웅,김낙성,김갑순,김정하,이종원,문장배,김인영,박용욱 한국분자세포생물학회 2013 Molecules and cells Vol.36 No.3
RANKL induces the formation of osteoclasts, which are responsible for bone resorption. Herein, we investigated the role of SWAP-70-like adapter of T cells (SLAT) in RANKL-induced osteoclastogenesis. Expression levels of SLAT were reduced during RANKL-induced osteoclastogenesis. Overexpression of SLAT in BMMs inhibited TRAP-positive multinuclear osteoclast formation and attenuated the expression of NFATc1, which is an important modulator in osteoclastogenesis. Furthermore, silencing of SLAT by RNA interference enhanced osteoclast formation as well as NFATc1 expression. In addition, SLAT was involved in RANKL-induced JNK activation in osteoclasts. Taken together, our data suggest that SLAT acts as a negative modulator of RANKL-induced osteoclastogenesis.
MicroRNA-26a Regulates RANKL-Induced Osteoclast Formation
김갑순,김낙성,김정하,김인영,이종원,성세문,박용욱 한국분자세포생물학회 2015 Molecules and cells Vol.38 No.1
Osteoclasts are unique cells responsible for the resorption of bone matrix. MicroRNAs (miRNAs) are involved in the regulation of a wide range of physiological processes. Here, we examined the role of miR-26a in RANKL-induced osteoclastogenesis. The expression of miR-26a was upregulated by RANKL at the late stage of osteoclastogenesis. Ectopic expression of an miR-26a mimic in osteoclast precursor cells attenuated osteoclast formation, actin-ring formation, and bone resorption by suppressing the expression of connective tissue growth factor/CCN family 2 (CTGF/ CCN2), which can promote osteoclast formation via upregulation of dendritic cell-specific transmembrane protein (DC-STAMP). On the other hand, overexpression of miR-26a inhibitor enhanced RANKL-induced osteoclast formation and function as well as CTGF expression. In addition, the inhibitory effect of miR-26a on osteoclast formation and function was prevented by treatment with recombinant CTGF. Collectively, our results suggest that miR-26a modulates osteoclast formation and function through the regulation of CTGF.
Bone Cell Communication Factors Provide a New Therapeutic Strategy for Osteoporosis
김정하,김낙성 전남대학교 의과학연구소 2020 전남의대학술지 Vol.56 No.2
Bone homeostasis is strictly regulated by the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Many studies have shown that osteoclasts affect osteoblasts, and vice versa, through diffusible paracrine factors, cell-cell contact, and cell-bone matrix interactions to achieve the correct balance between osteoclastic and osteoblastic activities in the basic multicellular unit (BMU). The strict regulation that occurs during bone remodeling hinders the long-term use of the currently available antiresorptive agents and anabolic agents for the treatment of osteoporosis. To overcome these limitations, it is necessary to develop novel agents that simultaneously inhibit bone resorption, promote bone formation, and decouple resorption from formation. Therefore, a more detailed understanding of the mechanisms involved in osteoclast-osteoblast communication during bone remodeling is necessary.
Signaling Pathways in Osteoclast Differentiation
김정하,김낙성 전남대학교 의과학연구소 2016 전남의대학술지 Vol.52 No.1
Osteoclasts are multinucleated cells of hematopoietic origin that are responsible forthe degradation of old bone matrix. Osteoclast differentiation and activity are controlledby two essential cytokines, macrophage colony-stimulating factor (M-CSF) andthe receptor activator of nuclear factor-B ligand (RANKL). M-CSF and RANKL bindto their respective receptors c-Fms and RANK to stimulate osteoclast differentiationthrough regulation of delicate signaling systems. Here, we summarize the critical oressential signaling pathways for osteoclast differentiation including M-CSF-c-Fms signaling,RANKL-RANK signaling, and costimulatory signaling for RANK.
김갑순,김낙성,김정하,Jang Bae Moon,Jongwon Lee,Han bok Kwak,Yong-Wook Park 한국분자세포생물학회 2012 Molecules and cells Vol.33 No.4
RANKL induces the formation of osteoclasts, which are responsible for bone resorption. Herein we investigate the role of the transmembrane adaptor proteins in RANKL-induced osteoclastogenesis. LAT positively regulates osteoclast differentiation and is up-regulated by RANKL via c-Fos and NFATc1, whereas LAB and LIME act as negative modulators of osteoclastogenesis. In addition, silencing of LAT by RNA interference or overexpression of a LAT dominant negative in bone marrow-derived macrophage cells attenuates RANKL-induced osteoclast formation. Furthermore, LAT is in-volved in RANKL-induced PLC activation and NFATc1 induction. Thus, our data suggest that LAT acts as a positive regulator of RANKL-induced osteoclastogenesis.