Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation

Ying Hua Cheng, R. Adam Hooker, Khanh Nguyen, Rita Gerard-O'Riley, David L. Waning, Brahmananda R. Chitteti, Tomas E. Meijome, Hui Lin Chua, Artur P. Plett, Christie M. Orschell, Edward F. Srour, Lindsey D. Mayo, Fredrick M. Pavalko, Angela Bruzzaniti, Melissa A. Kacena

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Preclinical and clinical evidence from megakaryocyte (MK)-related diseases suggests that MKs play a significant role in maintaining bone homeostasis. Findings from our laboratories reveal that MKs significantly increase osteoblast (OB) number through direct MK-OB contact and the activation of integrins. We, therefore, examined the role of Pyk2, a tyrosine kinase known to be regulated downstream of integrins, in the MK-mediated enhancement of OBs. When OBs were co-cultured with MKs, total Pyk2 levels in OBs were significantly enhanced primarily because of increased Pyk2 gene transcription. Additionally, p53 and Mdm2 were both decreased in OBs upon MK stimulation, which would be permissive of cell cycle entry. We then demonstrated that OB number was markedly reduced when Pyk2-/- OBs, as opposed to wild-type (WT) OBs, were co-cultured with MKs. We also determined that MKs inhibit OB differentiation in the presence and absence of Pyk2 expression. Finally, given that MK-replete spleen cells from GATA-1-deficient mice can robustly stimulate OB proliferation and bone formation in WT mice, we adoptively transferred spleen cells from these mice into Pyk2-/- recipient mice. Importantly, GATA-1-deficient spleen cells failed to stimulate an increase in bone formation in Pyk2-/- mice, suggesting in vivo the important role of Pyk2 in the MK-induced increase in bone volume. Further understanding of the signaling pathways involved in the MK-mediated enhancement of OB number and bone formation will facilitate the development of novel anabolic therapies to treat bone loss diseases.

Original languageEnglish (US)
Pages (from-to)1434-1445
Number of pages12
JournalJournal of Bone and Mineral Research
Issue number6
StatePublished - Jun 2013

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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