Today’s open access paper is an example of one of the less well known connections between processes of aging. Loss of efficiency of the cellular maintenance processes of autophagy is a characteristic of cells in old tissues. Here, researchers note that this dysfunction in the hematopoietic cells responsible for creating blood and immune cells also results in structure changes in bone marrow that contribute to the development of osteoporosis, the loss of bone mass and strength that occurs with age. Just because such connections are obscure doesn’t mean that they are unimportant.
Osteoporosis is the outcome of an imbalance between osteoblasts that create bone and osteoclasts that break down bone tissue. Both cell populations are constantly active throughout life; bone is a dynamically remodeled tissue. With age a number of processes lead to greater osteoclast activity – easy enough to point out, but difficult to pick apart the causes and decide on a point of intervention. Cellular senescence is a contributing factor, of course, as it contributes to near all age-related conditions. Here, reduced autophagy is proposed to interfere in maintenance of the osteoblast population.
There are a few types of autophagy, involving different ways of identifying and moving unwanted proteins and structures to be engulfed by a lysosome. A lysosome is a membrane-wrapped package of enzymes that can break down most of the molecules a cell will encounter. Exactly why autophagy declines with age is an interesting question. A great many papers cover what is known of proximate causes, changes in expression of protein machinery that regulates or is needed by different parts of the process, all of which seem to fail in their own way, as well as the accumulation of persistent metabolic waste in lysosomes, molecules that cannot be broken down by our biochemistry as it stands. The latter is fairly straightforward, but the changes in regulation and expression of proteins are ever a challenge to chase back to their underlying cause.
Previous studies on osteoporosis overwhelmingly focused on the etiology within bone tissue that locally induces the disease. In this study, we showed that osteoporosis is highly associated with reduction in hematopoietic autophagy activity in humans. We showed that an autophagy defect in the hematological system leads to severe bone loss. The disturbed osteocyte homeostasis is apparently caused by impaired type H blood vessels and possibly an aberrant alteration in the extracellular matrix (ECM) pathways that govern osteocyte homeostasis in hematopoietic autophagy-defective mice. Our results thus suggest that autophagy in the adjacent hematopoietic cells is essential to maintain bone homeostasis, and chronic hematopoietic autophagy deficiency can result in the development of osteoporosis in both mice and humans
While the osteal impact on hematopoiesis, in particular on the formation of bone marrow hematopoietic stem cell niches, is well documented, studies of hematopoietic regulation of osteocyte function have been inadequate. Hematopoietic regulation of osteoblast proliferation and differentiation was previously discussed largely with skepticism speculation. However, a recent study showed that loss of the hematopoietic stem cell factor GATA2 in the osteogenic lineage impairs trabecularization and mechanical strength of bone. Our present study of RNA sequencing revealed that impairment of hematopoietic cells by autophagy defect also led to enhanced iron activity, which may eventually lead to iron overload, a major cause of osteoporosis.
Hematopoietic cells and osteocytes are adjacent in the bone marrow niche environment. Normal hematopoiesis and bone homeostasis are interdependent. Men with low bone mineral density (BMD) or greater BMD loss have decreased circulating erythrocytes and lymphocytes and increased myeloid cells, and anemia or low blood cell counts are associated with declining BMD or increased fracture risk in the aged population. On the other hand, chronic disorders affecting hematopoiesis, such as sickle cell anemia and thalassemia, demonstrate clear skeletal phenotypes, including bone loss and increased fracture risk.
Bone marrow HSCs have been found to be capable of differentiating to osteoblasts through a mesenchymal intermediate. These findings suggest that the developmental capacity of HSCs is not restricted to hematopoietic lineages, but extends to osteogenic differentiation, possibly via the HSC potential to transdifferentiate to osteocytes. HSCs do not rest passively in their niche, but instead directly participate in bone formation and niche activities. Therefore, HSC functions and bone turnover are coupled in osteoporosis.
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.