ABSTRACT
C-Mpl is the receptor for thrombopoietin (TPO), the main megakaryocyte (MK) growth factor, and c-Mpl is believed to be expressed on cells of
the hematopoietic lineage. As MKs have been shown to enhance bone formation, it may be expected that mice in which c-Mpl was globally
knocked out (c-Mpl
/
mice) would have decreased bone mass because they have fewer MKs. Instead, c-Mpl
/
mice have a higher bone mass
than WT controls. Using c-Mpl
/
mice we investigated the basis for this discrepancy and discovered that c-Mpl is expressed on both
osteoblasts (OBs) and osteoclasts (OCs), an unexpected finding that prompted us to examine further how c-Mpl regulates bone. Static and
dynamic bone histomorphometry parameters suggest that c-Mpl deficiency results in a net gain in bone volume with increases in OBs and OCs.
In vitro, a higher percentage of c-Mpl
/
OBs were in active phases of the cell cycle, leading to an increased number of OBs. No difference in OB
differentiation was observed in vitro as examined by real-time PCR and functional assays. In co-culture systems, which allow for the
interaction between OBs and OC progenitors, c-Mpl
/
OBs enhanced osteoclastogenesis. Two of the major signaling pathways by which OBs
regulate osteoclastogenesis, MCSF/OPG/RANKL and EphrinB2-EphB2/B4, were unaffected in c-Mpl
/
OBs. These data provide new findings
for the role of MKs and c-Mpl expression in bone and may provide insight into the homeostatic regulation of bone mass as well as bone loss
diseases such as osteoporosis. J. Cell. Biochem. 9999: 1–11, 2015. ? 2015 Wiley Periodicals, Inc.