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

Tumor necrosis factor-related, activation-induced cytokine (TRANCE), a tumo r necrosis factor family member, mediates survival of dendritic cells in th e immune system and is required for osteoclast differentiation and activati on in the skeleton. We report the skeletal phenotype of TRANCE-deficient mi ce and its rescue by the TRANCE transgene specifically expressed in lymphoc ytes. TRANCE-deficient mice showed severe osteopetrosis, with no osteoclast s, marrow spaces, or tooth eruption, and exhibited profound growth retardat ion at several skeletal sites, including the limbs, skull, and vertebrae. T hese mice had marked chondrodysplasia, with thick, irregular growth plates and a relative increase in hypertrophic chondrocytes. Transgenic overexpres sion of TRANCE in lymphocytes of TRANCE-deficient mice rescued osteoclast d evelopment in two locations in growing long bones: excavation of marrow cav ities permitting hematopoiesis in the marrow spaces, and remodeling of oste opetrotic 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 w ere they present in tooth eruption pathways. These defects resulted in scle rotic metaphyses with persistence of club-shaped long bones and unerupted t eeth, and the growth plate defects were largely unimproved by the TRANCE tr ansgene. Thus, TRANCE-mediated regulation of the skeleton is complex, and i mpacts chondrocyte differentiation and osteoclast formation in a manner tha t likely requires local delivery of TRANCE.