Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene

Abstract

Tumor necrosis factor-related, activation-induced cytokine (TRANCE), a tumor necrosis factor family member, mediates survival of dendritic cells in the immune system and is required for osteoclast differentiation and activation in the skeleton. We report the skeletal phenotype of TRANCE-deficient mice and its rescue by the TRANCE transgene specifically expressed in lymphocytes. TRANCE-deficient mice showed severe osteopetrosis, with no osteoclasts, marrow spaces, or tooth eruption, and exhibited profound growth retardation at several skeletal sites, including the limbs, skull, and vertebrae. These mice had marked chondrodysplasia, with thick, irregular growth plates and a relative increase in hypertrophic chondrocytes. Transgenic overexpression of TRANCE in lymphocytes of TRANCE-deficient mice rescued osteoclast development in two locations in growing long bones: excavation of marrow cavities permitting hematopoiesis in the marrow spaces, and remodeling of osteopetrotic woven bone in the shafts of long bones into histologically normal lamellar bone. However, osteoclasts in these mice failed to appear at the chondroosseous junction and the metaphyseal periosteum of long bones, nor were they present in tooth eruption pathways. These defects resulted in sclerotic metaphyses with persistence of club-shaped long bones and unerupted teeth, and the growth plate defects were largely unimproved by the TRANCE transgene. Thus, TRANCE-mediated regulation of the skeleton is complex, and impacts chondrocyte differentiation and osteoclast formation in a manner that likely requires local delivery of TRANCE. T he skeleton is a dynamic system throughout life, balancing the need for physical support and locomotion on the one hand with the requirement for precisely regulated concentrations of circulating mineral ions on the other. These processes begin in utero and are coordinated with growth of the individual by a unique collaboration between the cells of cartilage and bone (1). The two principal cell types in bone are osteoblasts, which secrete bone matrix, and osteoclasts, which resorb bone, and the coupled actions of both are required for normal skeletal formation and maintenance and for mineral homeostasis (2, 3).Tumor necrosis factor-related, activation-induced cytokine (TRANCE) is a member of the tumor necrosis factor family that was initially discovered as a factor expressed on T cells that supports the survival and activity of antigen-presenting dendritic cells in the immune system (4-8). It was soon recognized that TRANCE was also the osteoclast differentiation factor produced by osteoblasts that plays an obligatory role in the formation and activation of osteoclasts, the multinucleated, monocytemacrophage lineage-derived cells that carry out bone resorption. The roles of TRANCE in the immune and skeletal systems were apparent in the phenotype of TRANCE null mice, which had severe osteopetrosis, lacked osteoclasts, and failed to form lymph nodes (7).The binding of TRANCE to its receptor (TRANCE-R), itself a member of the ...

Strength of TRAF6 signalling determines osteoclastogenesis

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