LAUSR

Defensins are small, cysteine-rich cationic proteins contained within cells of the immune system. The defensin peptides assist in killing phagocytosed bacteria in neutrophils and in many epithelial cell types. Most defensins function by binding to the microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients. The term “defensin” was coined in the 1980s, although perhaps the term “cationic antimicrobial proteins” would be better [1]. The underlying genes responsible for defensin production are highly polymorphic. Some aspects are conserved; however, the hallmarks of defensins are their small size, high density of cationic charge, and a six-cysteineresidue motif. In humans, two subfamilies of defensins are important, namely ɑ-defensin and β-defensin. The βdefensins are induced by different stimuli, including lipopolysaccharide, lipoteichoic acid, and bacterial DNA [2]. It appears that defensins can defend against more than just outside invaders. For instance, a defensin-like peptide is the cathelicidin-related antimicrobial peptide (CRAMP). CRAMP is expressed in salivary glands and in the oral mucosa. In Kostmann’s disease, a severe form of congenital neutropenia, CRAMP is deficient. The patients develop severe infections. However, they also feature remarkable loss of alveolar bone within the oral cavity. This connection suggested that CRAMP could possibly prevent the progression of periodontal disease, a hypothesis that has been addressed earlier. Although the earlier studies were not entirely convincing, the idea was proposed that CRAMP and the human analog LL-37 could serve as an osteoblast-derived protector in bacterial infection-induced osteoclastic bone reabsorption [3, 4]. In this issue of J Mol Med, Park and colleagues pursue this idea further by investigating humanβ-defensin-3 C-15 (HBD3) and any role that small peptide could have in inhibiting bone reabsorption by impairing osteoclast activity [5]. The authors first examined the effect of HBD3 on receptor activator of nuclear factor κ-B ligand (RANKL). RANKL has been identified to affect the immune system and control bone regeneration and remodeling. RANKL is an apoptosis regulator, a binding partner of osteoprotegerin (OPG), and a ligand for the receptor activator of nuclear factor κ-B (RANK). RANKL binds to RANK, which then binds to tumor necrosis factor (TNF)receptor associated factor-6 (TRAF6). TRAF6 stimulates the activation of the c-jun N-terminal kinase (JNK) and nuclear factor κ-B (NF-κB) pathways, which trigger differentiation and activation of multinucleated osteoclasts. The investigators found that RANKL increased the number of multinucleated osteoclast-like cells as expected. However, HBD3 inhibited the RANKLincreased TRAP-positive multinucleated cell formation (Fig. 1). In addition, HBD3 disrupted the formation of the RANKLinduced podosome belt, which is a feature typically found in mature osteoclasts with bone-resorbing capacity. Once activated, osteoclasts move to areas of microfracture in bone by chemotaxis. Lacunae are small spaces within bone containing an osteocyte in bone or chondrocyte in cartilage. They were named by John Howship (1781–1841), a British surgeon who first identified the structures. Osteoclasts can also reside in Howship’s lacunae, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclast’s plasma membrane to the underlying bone. Sealing zones are bounded by belts of specialized adhesion * Friedrich C. Luft [email protected]