Abstract
Hematopoietic disorders are known to increase the risk of complications such as osteoporosis. However, a direct link between hematopoietic cellular disorders and osteoporosis has been elusive. Here, we demonstrate that the deterioration of hematopoietic autophagy is coupled with osteoporosis in humans. With a conditional mouse model in which autophagy in the hematopoietic system is disrupted by deletion of the Atg7 gene, we show that incapacitating hematopoietic autophagy causes bone loss and perturbs osteocyte homeostasis. Induction of osteoporosis, either by ovariectomy, which blocks estrogen secretion, or by injection of ferric ammonium citrate to induce iron overload, causes dysfunction in the hematopoietic stem and progenitor cells (HSPCs) similar to that found in autophagy-defective mice. Transcriptomic analysis of HSPCs suggests promotion of iron activity and inhibition of osteocyte differentiation and calcium metabolism by hematopoietic autophagy defect, while proteomic profiling of bone tissue proteins indicates disturbance of the extracellular matrix pathway that includes collagen family members. Finally, screening for expression of selected genes and an immunohistological assay identifies severe impairments in H vessels in the bone tissue, which results in disconnection of osteocytes from hematopoietic cells in the autophagy-defective mice. We therefore propose that hematopoietic autophagy is required for the integrity of H vessels that bridge blood and bone cells and that its deterioration leads to osteoporosis.