Dynamin and PTP-PEST cooperatively regulate Pyk2 dephosphorylation in osteoclasts

Eleniste, Pierre P.; Du, Liping; Shivanna, Mahesh; Bruzzaniti, Angela

doi:10.1016/j.biocel.2012.01.022

Cited by 15 publications

(15 citation statements)

References 55 publications

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“…This is consistent with our previous report showing that Pyk2‐deficient mice have reduced osteoclast activity 19 as well as other studies showing that the Pyk2 chemical inhibitor protects against bone loss in ovariectomized rats 22 . Further, although we did not investigate root resorption, which is sometimes associated with RME, 31,32 the current study and published studies 16‐18,33‐35 demonstrate that Pyk2 deficiency reduces osteoclast activity, arguing against significant root resorption due to the higher resistance of the bony structures in Pyk2‐KO mice.…”

Section: Discussionsupporting

confidence: 92%

“…19,22 Further, genetic deletion or inhibition of Pyk2 impedes osteoclast actin ring formation and bone resorption. [16][17][18] Moreover, Pyk2 inhibition increased bone mass in ovariectomized rats 22 and prevented glucocorticoid-induced bone loss in mice, 23 largely due to anti-osteoclastic effects.…”

Section: Introductionmentioning

confidence: 95%

“…The tyrosine kinase Pyk2 is important for the actions of both osteoclasts [16][17][18][19] and osteoblasts. [20][21][22] In Pyk2 genetic knockout (Pyk2-KO) mice, osteoclast activity is inhibited 19 while osteoblast activity is increased, 22 leading to significantly elevated bone mass, trabecular number and trabecular thickness, compared to wild-type (WT) mice.…”

Section: Introductionmentioning

confidence: 99%

“…In Pyk2 genetic knockout (Pyk2‐KO) mice, osteoclast activity is inhibited 19 while osteoblast activity is increased, 22 leading to significantly elevated bone mass, trabecular number and trabecular thickness, compared to wild‐type (WT) mice 19,22 . Further, genetic deletion or inhibition of Pyk2 impedes osteoclast actin ring formation and bone resorption 16‐18 . Moreover, Pyk2 inhibition increased bone mass in ovariectomized rats 22 and prevented glucocorticoid‐induced bone loss in mice, 23 largely due to anti‐osteoclastic effects.…”

Section: Introductionmentioning

confidence: 99%

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Pyk2 deficiency enhances bone mass during midpalatal suture expansion

Sun

Eleniste

Utreja

et al. 2020

Orthod Craniofacial Res

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Objective: To determine if Pyk2 deficiency increases midpalatal suture bone mass and preserves sutural integrity after maxillary expansion. Setting and Sample: Thirty-six male Pyk2 knockout (KO) and control (WT) mice at 6 weeks of age. Materials and Methods: Mice received nickel-titanium spring expanders delivering 0 g (no intervention control), 10 or 20 g force for 14 days. High-resolution micro-CT was used to determine bone volume/tissue volume (BV/TV), sutural width and intermolar width. Effects on osteoclasts, chondrocytes and suture morphology were determined by histomorphometry. Results: Pyk2-KO controls (0 g) had 7% higher BV/TV compared with WT controls. Expanded Pyk2-KO maxillae also exhibited 12% (10 g) and 18% (20 g) higher BV/TV than WT mice. Although bone loss following expansion occurred in both genotypes, BV/TV was decreased to a greater extent in WT maxillae (−10% at 10g; −22% at 20 g) compared with Pyk2-KO maxillae (−11% only at 20 g). Expanded WT maxillae also showed a greater increase in sutural width, intermolar width and fibrous connective tissue width compared with expanded Pyk2-KO maxillae. Moreover, osteoclast number was increased 77% (10 g) and 132% (20 g) in expanded WT maxillae, but remained unchanged in expanded Pyk2-KO, compared to their respective controls. Cartilage area and chondrocyte number were increased to the same extent in expanded WT and Pyk2-KO sutures. Conclusions: These findings suggest that midpalatal suture expansion increases osteoclast formation in WT but not Pyk2-KO mice, leading to higher BV/TV in expanded Pyk2-KO maxillae. These studies suggest Pyk2-targeted strategies may be beneficial to increase bone density and preserve sutural integrity during maxillary expansion.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pyk2 deficiency enhances bone mass during midpalatal suture expansion

Sun

Eleniste

Utreja

et al. 2020

Orthod Craniofacial Res

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“…PTP-PEST is a ubiquitously-expressed cytosolic phosphatase that is involved in tyrosine dephosphorylation (Alonso et al, 2004, Veillette et al, 2009, Eleniste et al, 2012, Chellaiah et al, 2007). We first examined if dynamin could form a complex with PTP-PEST in osteoblasts and if dynamin GTPase activity was necessary for their interaction.…”

Section: Resultsmentioning

confidence: 99%

Osteoblast differentiation and migration are regulated by dynamin GTPase activity

Eleniste

Huang

Wayakanon

et al. 2014

The International Journal of Biochemistry & Cell Biology

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Bone formation is controlled by osteoblasts but the signaling proteins that control osteoblast differentiation and function are still unclear. We examined if the dynamin GTPase, which is associated with actin remodeling and migration in other cells, plays a role in osteoblast differentiation and migration. Dynamin mRNA was expressed in primary osteoblasts throughout differentiation (0-21 days). However, alkaline phosphatase (ALP) activity, a marker of osteoblast differentiation, was decreased in osteoblasts over-expressing dynamin. Conversely, ALP activity was increased following shRNA-mediated knockdown of dynamin and in osteoblasts treated with the dynamin inhibitor, dynasore. Dynasore also reduced c-fos and osterix expression, markers of early osteoblasts, suggesting a role for dynamin in pre-osteoblast to osteoblast differentiation. Since dynamin GTPase activity is regulated by tyrosine phosphorylation, we examined the mechanism of dynamin dephosphorylation in osteoblasts. Dynamin formed a protein complex with the tyrosine phosphatase PTP-PEST and inhibition of phosphatase activity increased the level of phosphorylated dynamin. Further, PTP-PEST blocked the Src-mediated increase in the phosphorylation and GTPase activity of wild-type dynamin but not the phosphorylation mutant dynY231F/Y597F. Although ALP activity was increased in osteoblasts expressing GTPasedefective dynK44A, and to a lesser extent dynY231F/Y597F, osteoblast migration was significantly inhibited by dynK44A and dynY231F/Y597F. These studies demonstrate a novel role for dynamin GTPase activity and phosphorylation in osteoblast differentiation and migration, which may be important for bone formation.

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Pyk2 and Megakaryocytes Regulate Osteoblast Differentiation and Migration Via Distinct and Overlapping Mechanisms

Eleniste¹,

Patel²,

Posritong³

et al. 2015

J of Cellular Biochemistry

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Osteoblast differentiation and migration are necessary for bone formation during bone remodeling. Mice lacking the proline-rich tyrosine kinase Pyk2 (Pyk2-KO) have increased bone mass, in part due to increased osteoblast proliferation. Megakaryocytes (MKs), the platelet-producing cells, also promote osteoblast proliferation in vitro and bone-formation in vivo via a pathway that involves Pyk2. In the current study, we examined the mechanism of action of Pyk2, and the role of MKs, on osteoblast differentiation and migration. We found that Pyk2-KO osteoblasts express elevated alkaline phosphatase (ALP), type I collagen and osteocalcin mRNA levels as well as increased ALP activity and mineralization, confirming that Pyk2 negatively regulates osteoblast function. Since Pyk2 Y402 phosphorylation is important for its catalytic activity and for its protein-scaffolding functions, we expressed the phosphorylation-mutant (Pyk2Y402F) and kinase-mutant (Pyk2K457A) in Pyk2-KO osteoblasts. Both Pyk2Y402F and Pyk2K457A reduced ALP activity, whereas only kinase-inactive Pyk2K457A inhibited Pyk2-KO osteoblast migration. Consistent with a role for Pyk2 on ALP activity, co-culture of MKs with osteoblasts led to a decrease in the level of phosphorylated Pyk2 (pY402) as well as a decrease in ALP activity. Although Pyk2-KO osteoblasts exhibited increased migration compared to WT osteoblasts, Pyk2 expression was not required for the ability of MKs to stimulate osteoblast migration. Together, these data suggest that osteoblast differentiation and migration are inversely regulated by MKs via distinct Pyk2-dependent and independent signaling pathways. Novel drugs that distinguish between the kinase-dependent or protein-scaffolding functions of Pyk2 may provide therapeutic specificity for the control of bone-related diseases.

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Dynamin and PTP-PEST cooperatively regulate Pyk2 dephosphorylation in osteoclasts

Cited by 15 publications

References 55 publications

Pyk2 deficiency enhances bone mass during midpalatal suture expansion

Pyk2 deficiency enhances bone mass during midpalatal suture expansion

Osteoblast differentiation and migration are regulated by dynamin GTPase activity

Pyk2 and Megakaryocytes Regulate Osteoblast Differentiation and Migration Via Distinct and Overlapping Mechanisms

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