Fig. 3

RANKL in biological processes other than bone metabolism and the immune systems. a RANKL–RANK interaction in the development of the mammary gland. The LECs of the mammary gland are divided into two subpopulations based on the expression of PR. PR-expressing LECs express RANKL in response to Pg. RANKL interacts with LECs and MECs, resulting in the proliferation of these epithelial cells and the morphogenesis of the gland. b RANKL–RANK interaction in thermogenesis. Certain types of cells of the LSn of the forebrain express RANKL, which interacts with neurons and astrocytes in the POA and the MSn. These nuclei produce PGE2 via COX-2, which leads to both shivering and non-shivering thermogenesis. c RANKL–RANK signaling in the blood vessel. Both RANKL and RANK are expressed on vascular cells including VSMCs. RANKL induces the expression of BMP2 and 4, which promotes the osteogenic gene expression of these cells, resulting in the vascular calcification. The signal is suppressed by estrogen and its receptor ERα. Expression of RANKL and RANK in this context is enhanced by Ang II. Production of Ang II is increased in turn by RANKL and RANK. d RANKL–RANK interaction in the hair cycle. Cells in the inner root sheath of the HF express RANKL. Cells in the outer root sheath, the bulge and the IFE express RANK. The interaction of these cells induces the growth of the epidermis and activates the hair cycle. e RANKL–RANK interaction in the liver. Hepatocytes stimulated with RANKL express pro-inflammatory cytokines that stimulate Kupffer cells, leading to T2DM. f RANKL–RANK interaction in the skeletal muscle. RANKL–RANK signaling in muscle fibers is involved in the strength and glucose metabolism of the skeletal muscle. RANKL receptor activator of NF-κB ligand, RANK receptor activator of NF-κB, Pg progesterone, PR progesterone receptor, LEC luminal epithelial cell, MEC myoepithelial cell, LSn lateral septal nucleus, POA preoptic area, MSn medial septal nucleus, PGE2 prostaglandin E2, COX-2 cyclooxygenase-2, VSMC vascular smooth muscle cell, BMP bone morphogenetic protein, ER estrogen receptor, Ang angiotensin, ATR angiotensin receptor, HF hair follicle, IFE interfollicular epidermis, T2DM type 2 diabetes mellitus