Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss

• Published in: Nature communications Vol. 9; no. 1; pp. 2909 - 7
• Main Authors: Xiong, Jinhu, Cawley, Keisha, Piemontese, Marilina, Fujiwara, Yuko, Zhao, Haibo, Goellner, Joseph J., O’Brien, Charles A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.07.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/31; 13/44; 42/44; 631/136/815; 631/443/63; 64/60; Animals; Biocompatibility; Bone loss; Bone mass; Bone remodeling; Bone Resorption - metabolism; Cancellous bone; Estrogens; Estrogens - metabolism; Female; Humanities and Social Sciences; Humans; Immune system; Lymph nodes; Lymph Nodes - metabolism; Lymphocytes; Mammary gland; Mammary Glands, Human - cytology; Mammary Glands, Human - metabolism; Membrane proteins; Mice; multidisciplinary; NF-κB protein; Osteoclasts - cytology; Osteoclasts - metabolism; Ovariectomy; Proteins; RANK Ligand - metabolism; Rodents; Science; Science (multidisciplinary); TRANCE protein; Tumor necrosis factor
• DOI: 10.1038/s41467-018-05244-y
• ISSN: 2041-1723

Receptor activator of NFkB ligand (RANKL) is a TNF-family cytokine required for osteoclast formation, as well as immune cell and mammary gland development. It is produced as a membrane-bound protein that can be shed to form a soluble protein. We created mice harboring a sheddase-resistant form of RANKL, in which soluble RANKL is undetectable in the circulation. Lack of soluble RANKL does not affect bone mass or structure in growing mice but reduces osteoclast number and increases cancellous bone mass in adult mice. Nonetheless, the bone loss caused by estrogen deficiency is unaffected by the lack of soluble RANKL. Lymphocyte number, lymph node development, and mammary gland development are also unaffected by the absence of soluble RANKL. These results demonstrate that the membrane-bound form of RANKL is sufficient for most functions of this protein but that the soluble form does contribute to physiological bone remodeling in adult mice. RANKL is a cytokine produced as a membrane-bound and a secreted protein. Here, using mice lacking soluble RANKL, the authors show that the secreted protein is important for osteoclast function, but not for mammary gland and lymphocyte development.