Stressed and Senescent Macrophages as an Important Cause of Postmenopausal Osteoporosis
Harmful changes in the behavior of the innate immune cells known as macrophages, and their analogous counterparts in the brain, called microglia, show up everywhere in investigations of aging and age-related disease. Macrophages are resident in all tissues, and participate in normal tissue maintenance and function in addition to chasing down pathogens and eliminating errant cells. Which activities are undertaken by a given macrophage are determined by its state; a crude division can be made between M1 macrophages that are pro-inflammatory and aggressive versus M2 macrophages that are anti-inflammatory and engage in tissue maintenance. Circumstances such as the level of damage in the tissue environment and level of inflammatory signaling will bias macrophages into one camp or the other.
The presence of too many inflammatory M1 macrophages may be an important feature of aging, a maladaptive reaction to rising levels of damage and inflammatory signaling - that signaling then further amplified by the macrophages themselves. But beyond this, there is also the question of cellular senescence. Cells become senescent in response to replication stress and mutational damage, as well as in response to tissue injury. These cells pump out inflammatory signaling but are efficiently removed by the immune system in youth. The immune system becomes less capable with age, and thus senescent cells accumulate. Many of these are macrophages. At some point all of this inflammation tips over into tissue dysfunction.
Today's open access paper is an example of the consequences of too many inflammatory and senescent macrophages. The researchers trace a path from the reduced estrogen production of menopause to excessive inflammatory and senescent macrophages in bone tissue, leading to disruption of the usual maintenance of bone. That in turn leads to an accelerated loss of bone density, manifesting as osteoporosis. Regular clearance of these errant macrophages, or some form of reprogramming to alter their state, may help to sever the link between menopause and osteoporosis, and slow the age-related decline of bone density.
Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence, and apoptotic process. Single cell RNA sequencing analysis revealed that osteal macrophages were heterogenously clustered into 6 subsets that expressed proliferative, inflammatory, anti-inflammatory, and efferocytosis gene signatures.
Importantly, postmenopausal mice exhibited a 20-fold increase in the subset that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopause altered the osteal macrophages subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment.
Furthermore, adoptive macrophage transfer onto calvarial bone was performed and mice that received oxidative-stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in development of inflammaging in bone microenvironment. Consistently, depletion of senescent cells and oxidative-stressed macrophages subset alleviated the excessive bone loss in postmenopausal mice. In conclusion, our data provided a new insight into the pathogenesis of osteoporosis and sheds light on a new therapeutic approach for the treatment/prevention of postmenopausal osteoporosis.