Abstract
RANKL signalization is implicated in the morphogenesis of various organs, including the skeleton. Mice invalidated for Rankl present an osteopetrotic phenotype that was less severe than anticipated, depending on RANKL’s implication in morphogenesis. The hypothesis of an attenuated phenotype, as a result of compensation during gestation by RANKL of maternal origin, was thus brought into question. In order to answer this question, Rankl null mutant pups from null mutant parents were generated, and the phenotype analyzed. The results validated the presence of a more severe osteopetrotic phenotype in the second-generation null mutant with perinatal lethality. The experiments also confirmed that RANKL signalization plays a part in the morphogenesis of skeletal elements through its involvement in cell-to-cell communication, such as in control of osteoclast differentiation. To conclude, we have demonstrated that the phenotype associated with Rankl invalidation is attenuated through compensation by RANKL of maternal origin.
Highlights
RANKL (TNFSF11) signalization is implicated in the development, histogenesis, and functional homeostasis of various tissues, lymphoid tissues, skin appendages and skeletal components [1,2,3,4,5,6,7,8]
It was unsurprising that loss of RANKL function was associated with osteoclast-poor osteopetrosis in young patients with RANKL mutations and in Rankl null mutant mice [1,5], as well as in monkeys or mice injected with a powerful RANKL-blocking antibody [25,26,27]
As part of the craniofacial skeleton develops during the second half of gestation, and taking into account that secreted forms of RANKL of maternal origin may be active in the embryo, the question of an attenuated craniofacial phenotype in first-generation Rankl null mutants was raised
Summary
RANKL (TNFSF11) signalization is implicated in the development, histogenesis, and functional homeostasis of various tissues, lymphoid tissues, skin appendages (hair, teeth, and mammary glands) and skeletal components [1,2,3,4,5,6,7,8]. On the contrary, when RANKL was overexpressed, for instance, when produced genetically in pigs [28] and mice [29], a severe osteolytic phenotype was observed that led to premature death This phenotype was in line with those associated with the gains in RANK function observed in patients with mutations (duplications) in the RANK signal peptide, leading to three seemingly homologous pathologies (familial expansile osteolysis, Paget disease of bone 2, expansile skeletal hyperphosphatasia) [30,31], as well as in mice overexpressing RANK [16,32]
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