Glucocorticoid-Induced Bone Fragility Is Prevented in Female Mice by Blocking Pyk2/Anoikis Signaling

Amy Sato, Meloney Cregor, Kevin McAndrews, Troy Li, Keith W. Condon, Lilian Plotkin, Teresita Bellido

Research output: Contribution to journalArticle

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Abstract

Excess of glucocorticoids (GCs) is a leading cause of bone fragility, and therapeutic targets are sorely needed. We report that genetic deletion or pharmacological inhibition of proline-rich tyrosine kinase 2 (Pyk2) prevents GC-induced bone loss by overriding GC effects of detachment-induced bone cell apoptosis (anoikis). In wild-type or vehicle-treated mice, GCs either prevented osteoclast apoptosis or promoted osteoblast/osteocyte apoptosis. In contrast, mice lacking Pyk2 [knockout (KO)] or treated with Pyk2 kinase inhibitor PF-431396 (PF) were protected. KO or PF-treated mice were also protected from GC-induced bone resorption, microarchitecture deterioration, and weakening of biomechanical properties. In KO and PF-treated mice, GC increased osteoclasts in bone and circulating tartrate-resistant acid phosphatase form 5b, an index of osteoclast number. However, bone surfaces covered by osteoclasts and circulating C-terminal telopeptides of type I collagen, an index of osteoclast function, were not increased. The mismatch between osteoclast number vs function induced by Pyk2 deficiency/inhibition was due to osteoclast detachment and anoikis. Further, GC prolongation of osteoclast lifespan was absent in KO and PF-treated osteoclasts, demonstrating Pyk2 as an intrinsic osteoclast-survival regulator. Circumventing Pyk2 activation preserves skeletal integrity by preventing GC effects on bone cell survival (proapoptotic for osteoblasts/osteocytes, antiapoptotic for osteoclasts) and GC-induced bone resorption. Thus, Pyk2/anoikis signaling as a therapeutic target for GC-induced osteoporosis.

Original languageEnglish (US)
Pages (from-to)1659-1673
Number of pages15
JournalEndocrinology
Volume160
Issue number7
DOIs
StatePublished - Jul 1 2019

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Anoikis
Osteoclasts
Glucocorticoids
Focal Adhesion Kinase 2
Bone and Bones
Osteocytes
Apoptosis
Bone Resorption
Osteoblasts
Mouse Ptk2b protein
Osteoporosis
Cell Survival

ASJC Scopus subject areas

  • Endocrinology

Cite this

Glucocorticoid-Induced Bone Fragility Is Prevented in Female Mice by Blocking Pyk2/Anoikis Signaling. / Sato, Amy; Cregor, Meloney; McAndrews, Kevin; Li, Troy; Condon, Keith W.; Plotkin, Lilian; Bellido, Teresita.

In: Endocrinology, Vol. 160, No. 7, 01.07.2019, p. 1659-1673.

Research output: Contribution to journalArticle

Sato, Amy ; Cregor, Meloney ; McAndrews, Kevin ; Li, Troy ; Condon, Keith W. ; Plotkin, Lilian ; Bellido, Teresita. / Glucocorticoid-Induced Bone Fragility Is Prevented in Female Mice by Blocking Pyk2/Anoikis Signaling. In: Endocrinology. 2019 ; Vol. 160, No. 7. pp. 1659-1673.
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