Receptor activator of NF-κB (RANK) stimulates the proliferation of epithelial cells of the epidermo-pilosebaceous unit

Abstract

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...

RANK Induces Epithelial–Mesenchymal Transition and Stemness in Human Mammary Epithelial Cells and Promotes Tumorigenesis and Metastasis

“…Similarly, it has been recently shown that RANK is expressed in several stem cells of the skin, and that RANK signaling activate the hair cycle and epidermal growth (28). The mechanism responsible for this RANK-induced expansion of stem cells remains unknown.…”

Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells

“…RANKL treatment has been reported to promote proliferation of mammary epithelial cells cultured ex vivo (Kim et al, 2006). Beyond mammary epithelium, recent evidence shows proliferative effects directed by RANKL in other tissues, including the hair follicle pilosebaceous gland (Duheron et al, 2011) and thymus (Lee et al, 2008). Addition of RL stimulated proliferation of NMuMG cells in a dose-dependent manner over 72 hours of culture (Fig.…”

RANKL/RANK: from bone loss to the prevention of breast cancer

“…The fully human monoclonal RANKL-blocking antibody denosumab has been developed and approved for the treatment of osteoporosis and skeletal related events in cancer [10], already benefiting tens of thousands of patients. Besides the crucial function in osteoclastogenesis, RANK and RANKL have been implicated in various other physiological processes including immunotolerance, organogenesis of the immune system [2,3], osteoimmunology [11], hair growth [12] or thermoregulation in the central nervous system [13]. For example, bone loss that frequently occurs under inflammatory conditions such as rheumatoid arthritis can be, in part, explained by RANKL-expressing activated T cells [14].…”