Abstract
Megakaryocytes (MKs) play key roles in regulating bone metabolism. To test the roles of MK-secreted factors, we investigated whether MK and promegakaryocyte (pro-MK) conditioned media (CM) may affect bone formation and resorption. K562 cell lines were differentiated into mature MKs. Mouse bone marrow macrophages were differentiated into mature osteoclasts, and MC3T3-E1 cells were used for osteoblastic experiments. Bone formation was determined by a calvaria bone formation assay in vivo. Micro-CT analyses were performed in the femurs of ovariectomized female C57B/L6 and Balb/c nude mice after intravenous injections of MK or pro-MK CM. MK CM significantly reduced in vitro bone resorption, largely due to suppressed osteoclastic resorption activity. Compared with pro-MK CM, MK CM suppressed osteoblastic differentiation, but stimulated its proliferation, resulting in stimulation of calvaria bone formation. In ovariectomized mice, treatment with MK CM for 4 weeks significantly increased trabecular bone mass parameters, such as bone volume fraction and trabecular thickness, in nude mice, but not in C57B/L6 mice. In conclusion, MKs may secrete anti-resorptive and anabolic factors that affect bone tissue, providing a novel insight linking MKs and bone cells in a paracrine manner. New therapeutic agents against metabolic bone diseases may be developed from MK-secreted factors.
Highlights
Bone metabolism is regulated mainly by the action of bone-resorbing osteoclasts and bone-forming osteoblasts
The K562 and mouse fetal liver cells were differentiated into MK with phorbol 12-myristate 13-acetate (PMA) and thrombopoietin (TPO), respectively
It has been already reported that MK conditioned media (CM) suppressed osteoclastogenesis and bone resorption[13,14,15], consistent with our results
Summary
Bone metabolism is regulated mainly by the action of bone-resorbing osteoclasts and bone-forming osteoblasts. On the contrary, decreased bone resorption and/or increased formation with pharmacological interventions can reverse these imbalances. A mouse model with increased MKs showed decreased osteoclast number and bone resorption[12]. It was reported that MK-derived secreting factors suppress bone resorption, at least in part. A mouse model with an increased number of splenic MKs without an alteration of bone marrow MKs showed high bone mass with decreased bone resorption[12]. To our knowledge, there is no report about an in vivo anti-osteoporotic effect of megakaryocyte-secreting factors, we tested it
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