Abstract
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.
Highlights
Receptor activator of NFkB ligand (RANKL) is a TNF-family cytokine required for osteoclast formation, as well as immune cell and mammary gland development
The successful eruption of teeth and normal bone mass of young Tnfsf11SR/SR mice suggests that sRANKL is not required for the majority of the osteoclast formation that occurs in growing mice
Soluble RANKL is not required for lymph node development or the development of T and B lymphocytes
Summary
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. Lymphocyte number, lymph node development, and mammary gland development are 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. The levels of circulating sRANKL are often elevated in conditions such as sex steroid deficiency, periodontitis, cancer, and inflammatory joint disease[7,8,9,10,11] It is unclear whether sRANKL is functionally involved in osteoclast formation in these or normal physiological conditions. We find that while most functions of RANKL are unaffected, osteoclast number is reduced and bone mass is increased in adult mice lacking sRANKL
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