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 Orschell, Edward Srour, Lindsey Mayo, Fredrick Pavalko, Angela Bruzzaniti, Melissa Kacena

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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
Pages (from-to)1434-1445
Number of pages12
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume28
Issue number6
DOIs
StatePublished - Jun 2013

Fingerprint

Megakaryocytes
Osteoblasts
Osteogenesis
Spleen
Integrins
Bone and Bones
Bone Diseases
Protein-Tyrosine Kinases
Cell Cycle
Homeostasis
Genes

Keywords

  • BONE FORMATION
  • MEGAKARYOCYTE
  • OSTEOBLASTS
  • PYK2

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation. / Cheng, Ying Hua; Hooker, R. Adam; Nguyen, Khanh; Gerard-O'Riley, Rita; Waning, David L.; Chitteti, Brahmananda R.; Meijome, Tomas E.; Chua, Hui Lin; Plett, Artur P.; Orschell, Christie; Srour, Edward; Mayo, Lindsey; Pavalko, Fredrick; Bruzzaniti, Angela; Kacena, Melissa.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 28, No. 6, 06.2013, p. 1434-1445.

Research output: Contribution to journalArticle

Cheng, Ying Hua ; Hooker, R. Adam ; Nguyen, Khanh ; Gerard-O'Riley, Rita ; Waning, David L. ; Chitteti, Brahmananda R. ; Meijome, Tomas E. ; Chua, Hui Lin ; Plett, Artur P. ; Orschell, Christie ; Srour, Edward ; Mayo, Lindsey ; Pavalko, Fredrick ; Bruzzaniti, Angela ; Kacena, Melissa. / Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation. In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013 ; Vol. 28, No. 6. pp. 1434-1445.
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abstract = "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.",
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AU - Cheng, Ying Hua

AU - Hooker, R. Adam

AU - Nguyen, Khanh

AU - Gerard-O'Riley, Rita

AU - Waning, David L.

AU - Chitteti, Brahmananda R.

AU - Meijome, Tomas E.

AU - Chua, Hui Lin

AU - Plett, Artur P.

AU - Orschell, Christie

AU - Srour, Edward

AU - Mayo, Lindsey

AU - Pavalko, Fredrick

AU - Bruzzaniti, Angela

AU - Kacena, Melissa

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