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Megakaryocytes promote osteoclastogenesis in aging
Deepa Kanagasabapathy1, Rachel J Blosser1, Kevin A Maupin1
1Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Aging
|July 8, 2020
Summary
Aging megakaryocytes (MKs) from female mice promote bone resorption by increasing osteoclast (OC) formation. This age-related shift in MK function, influenced by thrombopoietin (TPO) and RANKL, contributes to skeletal aging and bone loss.
Area of Science:
- Bone Biology
- Skeletal Aging
- Hematopoiesis
Background:
- Megakaryocytes (MKs) play a dual role in bone remodeling, stimulating osteoblasts (OBs) and inhibiting osteoclasts (OCs).
- Aging is associated with increased bone resorption and bone loss, but the impact of aging on MKs' regulation of OC formation remains unclear.
- Previous research focused on aging's effects on MK-mediated bone formation, leaving MK-mediated OC regulation understudied.
Purpose of the Study:
- To investigate the effect of aging on megakaryocyte (MK)-mediated osteoclast (OC) formation.
- To examine the influence of thrombopoietin (TPO) and MK-derived factors on OC precursors in young versus aged mice.
- To explore the role of sex hormones, specifically estrogen, in age-related changes in MK function.
Main Methods:
- Compared OC formation in vitro using conditioned media (CM) from young (3-4 months) and aged (22-25 months) mouse MKs.
- Assessed the expression of TPO receptor (Mpl) and circulating TPO levels in the bone marrow.
- Quantified RANKL expression in aged MKs and evaluated the impact of MK-derived factors on OC differentiation.
Main Results:
- Aging significantly increased in vitro OC formation.
- Elevated Mpl expression and circulating TPO levels were observed in aged bone marrow.
- MKs from aged female mice, unlike those from young mice, promoted OC formation and exhibited elevated RANKL expression, suggesting a role for estrogen.
Conclusions:
- Age-related changes in MKs, particularly in females, shift their function from inhibiting to promoting OC formation, contributing to increased bone resorption.
- Increased TPO-Mpl signaling and elevated RANKL expression in aged MKs drive osteoclastogenesis.
- These findings highlight a novel mechanism by which MKs impact skeletal aging and bone loss, with potential implications for therapeutic interventions.
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