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CTRP3 acts as a negative regulator of osteoclastogenesis through AMPK-c-Fos-NFATc1 signaling in vitro and RANKL-induced calvarial bone destruction in vivo.
Bone. 2015 Oct; 79:242-51.BONE

Abstract

Adipokines derived from adipocytes are important factors that act as circulating regulators of bone metabolism. C1q/tumor necrosis factor (TNF)-related Protein-3 (CTRP3) is a novel adipokine with multiple effects such as lowering glucose levels, inhibiting gluconeogenesis in the liver, and increasing angiogenesis and anti-inflammation. However, the effects and the mechanisms of CTRP3 on bone metabolism, which is regulated by osteoblasts and osteoclasts, have not been investigated. Here, we found that CTRP3 inhibited osteoclast differentiation induced by osteoclastogenic factors in bone marrow cell-osteoblast co-cultures, but did not affect the ratio of receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) to osteoprotegerin (OPG) induced by osteoclastogenic factors in osteoblasts. We also found that CTRP3 inhibited osteoclast differentiation from mouse bone marrow macrophages (BMMs) induced by RANKL in a dose-dependent manner without cytotoxicity. Functionally, CTRP3 inhibited the F-actin formation and bone resorbing activity of mature osteoclasts. Pretreatment with CTRP3 significantly inhibited RANKL-induced expression of c-Fos and nuclear factor of activated T-cells (NFATc1), essential transcription factors for osteoclast development. Surprisingly, the activation of AMP-activated protein kinase (AMPK) was considerably increased by pretreatment with CTRP3 for 1h. The CTRP3-stimulated AMPK activation was also maintained during RANKL-induced osteoclastogenesis. CTRP3 did not affect RANKL-induced p38, ERK, JNK, Akt, IκB, CREB, and calcium signaling (Btk and PLCγ2). These results suggest that CTRP3 plays an important role as a negative regulator of RANKL-mediated osteoclast differentiation by acting as an inhibitor of NFATc1 activation through the AMPK signaling pathway. Furthermore, CTRP3 treatment reduced RANKL-induced osteoclast formation and bone destruction in mouse calvarial bone in vivo based on micro-CT and histologic analysis. In conclusion, these findings strongly suggest that CTRP3 deserves new evaluation as a potential treatment target in various bone diseases associated with excessive osteoclast differentiation and bone destruction.

Authors+Show Affiliations

Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Department of Radiology, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Institute for Environmental Science, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Institute for Skeletal Disease, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea. Electronic address: ckhlms@wku.ac.kr.Imaging Science-based Lung and Bone Diseases Research Center, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea; Institute for Skeletal Disease, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea. Electronic address: jmoh@wku.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26103094

Citation

Kim, Ju-Young, et al. "CTRP3 Acts as a Negative Regulator of Osteoclastogenesis Through AMPK-c-Fos-NFATc1 Signaling in Vitro and RANKL-induced Calvarial Bone Destruction in Vivo." Bone, vol. 79, 2015, pp. 242-51.
Kim JY, Min JY, Baek JM, et al. CTRP3 acts as a negative regulator of osteoclastogenesis through AMPK-c-Fos-NFATc1 signaling in vitro and RANKL-induced calvarial bone destruction in vivo. Bone. 2015;79:242-51.
Kim, J. Y., Min, J. Y., Baek, J. M., Ahn, S. J., Jun, H. Y., Yoon, K. H., Choi, M. K., Lee, M. S., & Oh, J. (2015). CTRP3 acts as a negative regulator of osteoclastogenesis through AMPK-c-Fos-NFATc1 signaling in vitro and RANKL-induced calvarial bone destruction in vivo. Bone, 79, 242-51. https://doi.org/10.1016/j.bone.2015.06.011
Kim JY, et al. CTRP3 Acts as a Negative Regulator of Osteoclastogenesis Through AMPK-c-Fos-NFATc1 Signaling in Vitro and RANKL-induced Calvarial Bone Destruction in Vivo. Bone. 2015;79:242-51. PubMed PMID: 26103094.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CTRP3 acts as a negative regulator of osteoclastogenesis through AMPK-c-Fos-NFATc1 signaling in vitro and RANKL-induced calvarial bone destruction in vivo. AU - Kim,Ju-Young, AU - Min,Jung-Youl, AU - Baek,Jong Min, AU - Ahn,Sung-Jun, AU - Jun,Hong Young, AU - Yoon,Kwon-Ha, AU - Choi,Min Kyu, AU - Lee,Myeung Su, AU - Oh,Jaemin, Y1 - 2015/06/21/ PY - 2015/02/10/received PY - 2015/06/15/revised PY - 2015/06/16/accepted PY - 2015/6/24/entrez PY - 2015/6/24/pubmed PY - 2016/5/14/medline KW - AMPK KW - Adipokine KW - Bone resorption KW - CTRP3 KW - Osteoclast differentiation SP - 242 EP - 51 JF - Bone JO - Bone VL - 79 N2 - Adipokines derived from adipocytes are important factors that act as circulating regulators of bone metabolism. C1q/tumor necrosis factor (TNF)-related Protein-3 (CTRP3) is a novel adipokine with multiple effects such as lowering glucose levels, inhibiting gluconeogenesis in the liver, and increasing angiogenesis and anti-inflammation. However, the effects and the mechanisms of CTRP3 on bone metabolism, which is regulated by osteoblasts and osteoclasts, have not been investigated. Here, we found that CTRP3 inhibited osteoclast differentiation induced by osteoclastogenic factors in bone marrow cell-osteoblast co-cultures, but did not affect the ratio of receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) to osteoprotegerin (OPG) induced by osteoclastogenic factors in osteoblasts. We also found that CTRP3 inhibited osteoclast differentiation from mouse bone marrow macrophages (BMMs) induced by RANKL in a dose-dependent manner without cytotoxicity. Functionally, CTRP3 inhibited the F-actin formation and bone resorbing activity of mature osteoclasts. Pretreatment with CTRP3 significantly inhibited RANKL-induced expression of c-Fos and nuclear factor of activated T-cells (NFATc1), essential transcription factors for osteoclast development. Surprisingly, the activation of AMP-activated protein kinase (AMPK) was considerably increased by pretreatment with CTRP3 for 1h. The CTRP3-stimulated AMPK activation was also maintained during RANKL-induced osteoclastogenesis. CTRP3 did not affect RANKL-induced p38, ERK, JNK, Akt, IκB, CREB, and calcium signaling (Btk and PLCγ2). These results suggest that CTRP3 plays an important role as a negative regulator of RANKL-mediated osteoclast differentiation by acting as an inhibitor of NFATc1 activation through the AMPK signaling pathway. Furthermore, CTRP3 treatment reduced RANKL-induced osteoclast formation and bone destruction in mouse calvarial bone in vivo based on micro-CT and histologic analysis. In conclusion, these findings strongly suggest that CTRP3 deserves new evaluation as a potential treatment target in various bone diseases associated with excessive osteoclast differentiation and bone destruction. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/26103094/CTRP3_acts_as_a_negative_regulator_of_osteoclastogenesis_through_AMPK_c_Fos_NFATc1_signaling_in_vitro_and_RANKL_induced_calvarial_bone_destruction_in_vivo_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(15)00247-1 DB - PRIME DP - Unbound Medicine ER -