Receptor activator of NF-κB (RANK), known for controlling bone mass, has been recognized for its role in epithelial cell activation of the mammary gland. Because bone and the epidermo-pilosebaceous unit of the skin share a lifelong renewal activity where similar molecular players operate, and because mammary glands and hair follicles are both skin appendages, we have addressed the function of RANK in the hair follicle and the epidermis. Here, we show that mice deficient in RANK ligand (RANKL) are unable to initiate a new growth phase of the hair cycle and display arrested epidermal homeostasis. However, transgenic mice overexpressing RANK in the hair follicle or administration of recombinant RANKL both activate the hair cycle and epidermal growth. RANK is expressed by the hair follicle germ and bulge stem cells and the epidermal basal cells, cell types implicated in the renewal of the epidermopilosebaceous unit. RANK signaling is dispensable for the formation of the stem cell compartment and the inductive hair follicle mesenchyme, and the hair cycle can be rescued by Rankl knockout skin transplantation onto nude mice. RANKL is actively transcribed by the hair follicle at initiation of its growth phase, providing a mechanism for stem cell RANK engagement and hair-cycle entry. Thus, RANK-RANKL regulates hair renewal and epidermal homeostasis and provides a link between these two activities.R eceptor activator of NF-κB (RANK), a member of the TNF receptor family (TNFRSF11a), was originally identified as a regulator of bone density. Mice deficient in Rank or Rankl display increased bone density owing to reduced osteoclast formation, but the loss of the RANK ligand (RANKL) decoy receptor osteoprotegerin (OPG) results in lower bone mass because of unchecked RANK activation (1, 2).RANK has emerged as an important player in epithelial cell growth and differentiation. It is required for the formation of lactating mammary glands (3, 4), thymic medullary epithelial cells (5), and intestinal microfold cells (6) and has been implicated in the growth and metastasis of prostate (7) and mammary epithelial cancers (8, 9). Thus, RANK affects a great variety of epithelial cells of different organs. The skin is the largest epithelial surface, and its epidermo-pilosebaceous unit comprises the interfollicular epidermis (IFE), the hair follicle (HF), and the sebaceous gland. The HF has the particularity of undergoing cycles of growth (anagen), regression (catagen), and relative quiescence (telogen) (10), making it an excellent system for studying epidermal (stem) cells and organ remodeling (11)(12)(13)(14). Each HF is composed of a permanent upper portion, which includes the sebaceous gland and the bulge region, and a temporary lower cycling portion. The local balance of hair growth stimulators and inhibitors is critical for initiation of new hair growth (15-17). Intriguingly, many of these molecular players also operate in bone development and remodeling (e.g., members of the TGF-β superfamily and their antagonists, parathyroid hormo...

Systemic Lupus Erythematosus (SLE) is a severe systemic autoimmune disease, characterized by multi-organ damages, triggered by an autoantibody-mediated inflammation, and with a complex genetic influence. It is today accepted that adult SLE arises from the building up of many subtle gene variations, each one adding a new brick on the SLE susceptibility and contributing to a phenotypic trait to the disease. One of the ways to find these gene variations consists in comprehensive analysis of gene expression variation in a precise cell type, which can constitute a good complementary strategy to genome wide association studies. Using this strategy, and considering the central role of B cells in SLE, we analyzed the B cell transcriptome of quiescent SLE patients, and identified an overexpression of FKBP11, coding for a cytoplasmic putative peptidyl-prolyl cis/trans isomerase and chaperone enzyme. To understand the consequences of FKBP11 overexpression on B cell function and on autoimmunity's development, we created lentiviral transgenic mice reproducing this gene expression variation. We showed that high expression of Fkbp11 reproduces by itself two phenotypic traits of SLE in mice: breakdown of B cell tolerance against DNA and initiation of plasma cell differentiation by acting upstream of Pax5 master regulator gene.