The Role of RANKL (TRANCE/TNFSF11), a Tumor Necrosis Factor Family Member, in Skeletal Development: Effects of Gene Knockout and Transgenic Rescue

Abstract

We report the skeletal manifestations of restoring RANKL (TNFSF11/TRANCE; see foot note on nomenclature) expression in null mice using a lymphocyte-specific promoter. RANKL was discovered independently by immunologists and bone researchers by virtue of its essential roles in lymph node organogenesis, normal cellular immunity, and osteoclastogenesis. "Rescue" of RANKL knockout mice by a T- and B-cell expressed transgene reversed many immunological manifestations of the knockout, while it had highly selective effects on the skeletal pathology. RANKL-null mice exhibit severe osteopetrosis, no tooth eruption, markedly reduced skeletal growth, and growth plate chondrodystrophy. The transgene induced tartrate-resistant acid phosphatase (TRAP) positive cells in long bones as early as 3 days postpartum, restored marrow spaces in long bones, produced lamellar bone in the diaphyses, and restored osteoclasts at many endosteal sites, but not in periosteum nor the jaws. It did not improve the chondrodystrophy, chondroosseous junction defects, or tooth eruption. The ends of limb and axial skeletal elements remained highly sclerotic while diaphyses became osteopenic, and growth retardation persisted. Together, these results demonstrate the importance of local delivery of RANKL for many skeletal processes.

The expression of osteoprotegerin is required for maintaining the intervertebral disc endplate of aged mice

“…However, until now, there is no function assay or specific marker available to distinguish chondroclasts from osteoclasts. Interestingly, mice with osteoclast deficient, such as c-fos [18], RANK [19], RANKL [20] and NF-κB p50/p52 double knockout mice [21], are often dwarfed and have abnormal growth plate phenotype, linking osteoclasts or/and chondroclasts to cartilage remodeling.…”

The cast of clasts: catabolism and vascular invasion during bone growth, repair, and disease by osteoclasts, chondroclasts, and septoclasts

“…Most osteoclast-rich osteopetrotic mice have normal-looking growth plates (e.g., cathepsin K, c-src, and ClC7), while osteoclast-poor mutants (e.g., CSF-1, c-fms, RANK, RANKL, or TRAF-6 mutations) show failure of capillary invasion of the COJ and resultant accumulation of growth plate cartilage (8, 60, 75, 76). Together, these observations imply that a trophic factor or factors required for capillary invasion, specifically for recruitment of active septoclasts to the site, depend on the same CSF-1/RANKL pathway needed for osteoclastogenesis.…”

“…The most likely factor is of course VEGF. Since osteoclasts are present in the immediate vicinity of the growth plate in CSF-1 injected tl/tl rats and in RANKL knockout mice carrying a lymphocyte-specific rescue allele (67, 76), but there is no establishment of vascularization of the growth plate, clearly osteoclasts themselves are not sufficient to recruit vessels. It may be that CSF-1 and/or RANKL regulate VEGF expression by growth plate chondrocytes in an autocrine or paracrine manner.…”

RANKL Cytokine: From Pioneer of the Osteoimmunology Era to Cure for a Rare Disease

“…The strongest evidence for the role of RANKL during osteoclastogenesis came from gene inactivation in murine models [38–40], leading to osteoclast-poor osteopetrosis already present at birth. At 1 month of age, Rankl −/− mice were severely growth retarded due to poor nutrition secondary to lack of tooth eruption and displayed shortened long bones with club-shaped ends, thinning of the calvariae, generalized increase in bone density with very little marrow space, marked chondrodysplasia with thick, irregular growth plates, and relative increase in hypertrophic chondrocytes.…”