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RGS18 acts as a negative regulator of osteoclastogenesis by modulating the acid-sensing OGR1/NFAT signaling pathway.
J Bone Miner Res. 2007 Oct; 22(10):1612-20.JB

Abstract

We showed that RGS18, a myeloid lineage-specific RGS protein that is inhibited after activation of the RANK/RANKL system, is a negative regulator of osteoclastogenesis. RGS18 acts through an external acidosis-sensing osteoclastogenic mechanism through the OGR1/NFAT pathway.

INTRODUCTION

Osteoclasts are bone-resorbing multinuclear giant cells that are differentiated from mononuclear macrophage/monocyte lineage precursors stimulated by the RANK/RANKL system. The regulators of G-protein signaling (RGS) family is a diverse group of proteins that accelerate intrinsic GTP hydrolysis on heterotrimeric G-protein alpha subunits and play crucial roles in physiological regulation of G-protein-mediated cell signaling in various tissues and organs. We examined the expression and function of RGS18, a myeloid lineage-specific RGS protein, during osteoclastogenesis.

MATERIALS AND METHODS

A macrophage/monocyte lineage cell line, RAW264.7, and primary osteoclast precursor monocytes derived from mouse bone marrow cultured with macrophage-colony stimulating factor (M-CSF) (bone marrow-derived monocytes [BMMs]) were used in this study. Both cell types differentiate into osteoclast-like cells on activation by RANKL. Expression of different RGS proteins, including RGS18, was assessed by gene-specific RT-PCR. The subcellular distribution of RGS18 on native osteoclasts in bone tissues, as well as in RAW264.7 cells, was examined by immunohistochemistry using a specific polyclonal antibody. Short interfering RNA against RGS18 was used to inhibit the function endogenous RGS18 in these cell types. Activation of NFATc1, an osteoclastogenic transcription factor, on external acidosis was assessed by visualizing the nuclear localization of NFATc1 visualized with anti-NFATc1 antibody.

RESULTS

RAW264.7 and BMM cells both expressed mRNA for 10 different mammalian RGS proteins, including RGS18. Expression of RGS18 is significantly inhibited by RANKL both cell types, and inhibition of RGS18 function using RNA interference prominently enhanced osteoclastogenesis on stimulation with RANKL. The effect of RGS18 inhibition was reversed by blocking of proton-sensing OGR1 signaling, and overexpression of exogenous RGS18 inhibited extracellular acidosis-mediated NFATc1 activation. Immunohistochemical studies of mouse bone tissues revealed expression of RGS18 in osteoclasts in vivo.

CONCLUSIONS

RGS18 acts as a negative regulator of the acidosis-induced osteoclastogenic OGR1/NFAT signaling pathway, and RANKL stimulates osteoclastogenesis by inhibiting expression of RGS18. Therefore, the results suggest a novel control mechanism of osteoclastogenesis by RGS proteins.

Authors+Show Affiliations

Department of Clinical Research, National Hospital Organization, Osaka, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

17576169

Citation

Iwai, Kaori, et al. "RGS18 Acts as a Negative Regulator of Osteoclastogenesis By Modulating the Acid-sensing OGR1/NFAT Signaling Pathway." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 22, no. 10, 2007, pp. 1612-20.
Iwai K, Koike M, Ohshima S, et al. RGS18 acts as a negative regulator of osteoclastogenesis by modulating the acid-sensing OGR1/NFAT signaling pathway. J Bone Miner Res. 2007;22(10):1612-20.
Iwai, K., Koike, M., Ohshima, S., Miyatake, K., Uchiyama, Y., Saeki, Y., & Ishii, M. (2007). RGS18 acts as a negative regulator of osteoclastogenesis by modulating the acid-sensing OGR1/NFAT signaling pathway. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 22(10), 1612-20.
Iwai K, et al. RGS18 Acts as a Negative Regulator of Osteoclastogenesis By Modulating the Acid-sensing OGR1/NFAT Signaling Pathway. J Bone Miner Res. 2007;22(10):1612-20. PubMed PMID: 17576169.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RGS18 acts as a negative regulator of osteoclastogenesis by modulating the acid-sensing OGR1/NFAT signaling pathway. AU - Iwai,Kaori, AU - Koike,Masato, AU - Ohshima,Shiro, AU - Miyatake,Kunio, AU - Uchiyama,Yasuo, AU - Saeki,Yukihiko, AU - Ishii,Masaru, PY - 2007/6/20/pubmed PY - 2008/1/9/medline PY - 2007/6/20/entrez SP - 1612 EP - 20 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 22 IS - 10 N2 - UNLABELLED: We showed that RGS18, a myeloid lineage-specific RGS protein that is inhibited after activation of the RANK/RANKL system, is a negative regulator of osteoclastogenesis. RGS18 acts through an external acidosis-sensing osteoclastogenic mechanism through the OGR1/NFAT pathway. INTRODUCTION: Osteoclasts are bone-resorbing multinuclear giant cells that are differentiated from mononuclear macrophage/monocyte lineage precursors stimulated by the RANK/RANKL system. The regulators of G-protein signaling (RGS) family is a diverse group of proteins that accelerate intrinsic GTP hydrolysis on heterotrimeric G-protein alpha subunits and play crucial roles in physiological regulation of G-protein-mediated cell signaling in various tissues and organs. We examined the expression and function of RGS18, a myeloid lineage-specific RGS protein, during osteoclastogenesis. MATERIALS AND METHODS: A macrophage/monocyte lineage cell line, RAW264.7, and primary osteoclast precursor monocytes derived from mouse bone marrow cultured with macrophage-colony stimulating factor (M-CSF) (bone marrow-derived monocytes [BMMs]) were used in this study. Both cell types differentiate into osteoclast-like cells on activation by RANKL. Expression of different RGS proteins, including RGS18, was assessed by gene-specific RT-PCR. The subcellular distribution of RGS18 on native osteoclasts in bone tissues, as well as in RAW264.7 cells, was examined by immunohistochemistry using a specific polyclonal antibody. Short interfering RNA against RGS18 was used to inhibit the function endogenous RGS18 in these cell types. Activation of NFATc1, an osteoclastogenic transcription factor, on external acidosis was assessed by visualizing the nuclear localization of NFATc1 visualized with anti-NFATc1 antibody. RESULTS: RAW264.7 and BMM cells both expressed mRNA for 10 different mammalian RGS proteins, including RGS18. Expression of RGS18 is significantly inhibited by RANKL both cell types, and inhibition of RGS18 function using RNA interference prominently enhanced osteoclastogenesis on stimulation with RANKL. The effect of RGS18 inhibition was reversed by blocking of proton-sensing OGR1 signaling, and overexpression of exogenous RGS18 inhibited extracellular acidosis-mediated NFATc1 activation. Immunohistochemical studies of mouse bone tissues revealed expression of RGS18 in osteoclasts in vivo. CONCLUSIONS: RGS18 acts as a negative regulator of the acidosis-induced osteoclastogenic OGR1/NFAT signaling pathway, and RANKL stimulates osteoclastogenesis by inhibiting expression of RGS18. Therefore, the results suggest a novel control mechanism of osteoclastogenesis by RGS proteins. SN - 0884-0431 UR - https://www.unboundmedicine.com/medline/citation/17576169/RGS18_acts_as_a_negative_regulator_of_osteoclastogenesis_by_modulating_the_acid_sensing_OGR1/NFAT_signaling_pathway_ L2 - https://doi.org/10.1359/jbmr.070612 DB - PRIME DP - Unbound Medicine ER -