Abstract
Megakaryocytes (MKs) support bone formation by stimulating osteoblasts (OBs) and inhibiting osteoclasts (OCs). Aging results in higher bone resorption, leading to bone loss. Whereas previous studies showed the effects of aging on MK-mediated bone formation, the effects of aging on MK-mediated OC formation is poorly understood. Here we examined the effect of thrombopoietin (TPO) and MK-derived conditioned media (CM) from young (3-4 months) and aged (22-25 months) mice on OC precursors. Our findings showed that aging significantly increased OC formation in vitro. Moreover, the expression of the TPO receptor, Mpl, and circulating TPO levels were elevated in the bone marrow cavity. We previously showed that MKs from young mice secrete factors that inhibit OC differentiation. However, rather than inhibiting OC development, we found that MKs from aged mice promote OC formation. Interestingly, these age-related changes in MK functionality were only observed using female MKs, potentially implicating the sex steroid, estrogen, in signaling. Further, RANKL expression was highly elevated in aged MKs suggesting MK-derived RANKL signaling may promote osteoclastogenesis in aging. Taken together, these data suggest that modulation in TPO-Mpl expression in bone marrow and age-related changes in the MK secretome promote osteoclastogenesis to impact skeletal aging.
Highlights
Bone remodeling is a continuous and highly synchronized process which occurs throughout the lifetime of an individual
In vitro osteoclastogenesis was performed by culturing these cells with the necessary OC cytokines, receptor activator of nuclear factor kappa-Β ligand (RANKL) (80 ng/ml) and macrophage colony stimulating factor (M-CSF) (20 ng/ml)
Together with the increase in bone marrow MK numbers in aged mice (Figure 2A), these findings suggest that the increase in MK number with aging may be the result of increased megakaryopoiesis, which is supported by our previous studies [21]
Summary
Bone remodeling is a continuous and highly synchronized process which occurs throughout the lifetime of an individual. The activities of the bone cells, including osteoclasts (OCs) and osteoblasts (OBs) become dysregulated, with osteoclast activity exceeding osteoblastic bone formation, leading to bone loss. Both females and males experience osteoporosis in aging, postmenopausal women suffer higher bone resorption levels due to low estrogen levels [1,2,3]. Mice with elevated MK numbers exhibit up to a 3-fold increase in bone mass in vivo, which is attributed in part to MK-stimulated OB proliferation [6, 11, 15, 20]. The MK-mediated www.aging-us.com stimulation of OB proliferation and bone formation is impaired with aging, despite the marked increase in MK number in vivo, suggesting that aged MKs have decreased capacity to stimulate bone formation [21]
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