Abstract
Ribs are primarily made of cortical bone and are necessary for chest expansion and ventilation. Rib fractures represent the most common type of non-traumatic fractures in the elderly yet few studies have focused on the biology of rib fragility. Here, we show that deletion of βcatenin in Col1a2 expressing osteoblasts of adult mice leads to aggressive osteoclastogenesis with increased serum levels of the osteoclastogenic cytokine RANKL, extensive rib resorption, multiple spontaneous rib fractures and chest wall deformities. Within days of osteoblast specific βcatenin deletion, animals die from respiratory failure with a vanishing rib cage that is unable to sustain ventilation. Increased bone resorption is also observed in the vertebrae and femur. Treatment with the bisphosphonate pamidronate delayed but did not prevent death or associated rib fractures. In contrast, administration of the glucocorticoid dexamethasone decreased serum RANKL and slowed osteoclastogenesis. Dexamethasone preserved rib structure, prevented respiratory compromise and strikingly increased survival. Our findings provide a novel model of accelerated osteoclastogenesis, where deletion of osteoblast βcatenin in adults leads to rapid development of destructive rib fractures. We demonstrate the role of βcatenin dependent mechanisms in rib fractures and suggest that glucocorticoids, by suppressing RANKL, may have a role in treating bone loss due to aggressive osteoclastogenesis.
Highlights
While studying the role of bcatenin in regulating lineage and function of cells of mesenchymal origin, we observed that deletion of bcatenin in osteoblasts of adult mice led to rapid development of spontaneous rib fractures, flail chest and death from respiratory insufficiency. bcatenin was deleted in osteoblasts by crossing transgenic mice expressing tamoxifen inducible Cre recombinase driven by the Col1a2 promoter (Col1a2CreERT) with mice having both bcatenin alleles floxed [20,21]
Our study demonstrates a remarkable phenotype of aggressive osteoclastogenesis of the thoracic cage within days of osteoblast specific deletion of bcatenin that results in a disappearing thoracic skeleton incapable of supporting ventilation and life
Site specific bone resorption might depend on pathological RANKL expression by local osteoblasts, rather than by the secretion of RANKL by matrix embedded bone osteocytes thought to be predominant during unloading-associated osteoclastogenesis in trabecular bone [26] or in remodeling associated with normal skeletal development [27]
Summary
While studying the role of bcatenin in regulating lineage and function of cells of mesenchymal origin, we observed that deletion of bcatenin in osteoblasts of adult mice led to rapid development of spontaneous rib fractures, flail chest and death from respiratory insufficiency. Lineage analysis using the Col1a2CreERT:R26RlacZ reporter mice demonstrated that in addition to osteoblasts in bone, smooth muscle cells and fibroblasts in the heart, lung, liver, spleen, skeletal muscle and kidney expressed Col1a2 (Figure S1).
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