Megakaryocytes Regulate Expression of Pyk2 Isoforms and Caspase-mediated Cleavage of Actin in Osteoblasts

Kacena, Melissa A.; Eleniste, Pierre P.; Cheng, Ying‐Hua; Huang, Su; Shivanna, Mahesh; Meijome, Tomas E.; Mayo, Lindsey D.; Bruzzaniti, Angela

doi:10.1074/jbc.m111.309880

Cited by 26 publications

(49 citation statements)

References 64 publications

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“…21 Fetuses were dissected from pregnant mice at embryonic day 13-15. The livers were removed, and single-cell suspensions were made by forcing cells through sequentially smaller gauge needles (18,20, and 23 gauge).…”

Section: Preparation Of Fetal Liver-derived Megakaryocytesmentioning

confidence: 99%

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Osteomacs interact with megakaryocytes and osteoblasts to regulate murine hematopoietic stem cell function

Mohamad¹,

Xu²,

Ghosh³

et al. 2017

Blood Advances

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Section: Preparation Of Fetal Liver-derived Megakaryocytesmentioning

confidence: 99%

“…21 Calvariae from 2-to 3-day-old neonatal mice were pretreated with 10 mM EDTA in phosphate-buffered saline (PBS) for 30 minutes. Calvariae were then subjected to sequential collagenase digestions (200 U/mL; Collagenase, Type 2, Worthington Biochemicals, Lakewood NJ).…”

Section: Preparation Of Fresh Nccsmentioning

confidence: 99%

Osteomacs interact with megakaryocytes and osteoblasts to regulate murine hematopoietic stem cell function

Mohamad¹,

Xu²,

Ghosh³

et al. 2017

Blood Advances

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“…Our group as well as others have been working to understand how MKs regulate bone mass. We previously reported that MKs, co-cultured with OBs, were able to stimulate OB proliferation (Kacena, et al, 2004, Ciovacco, et al, 2009, Ciovacco, et al, 2010, Lemieux, et al, 2010, Kacena, et al, 2012, Cheng, et al, 2013). Of note, Miao et al (Miao, et al, 2004) demonstrated the bone marrow stromal cell aggregates containing MKs expressed higher levels of alkaline phosphatase than did single cell suspensions.…”

Section: Discussionmentioning

confidence: 99%

“…Surviving host MKs migrate to endosteal surfaces in bone where they stimulate a 2-fold increase in OB number thus augmenting the so-called endosteal hematopoietic stem cell niches. Contact between MKs and OBs and/or their precursors have been described (Cheng, et al, 2000, Miao, et al, 2004, Kacena, et al, 2004, Ciovacco, et al, 2009, Ciovacco, et al, 2010, Lemieux, et al, 2010, Dominici, et al, 2009, Kacena, et al, 2012, Cheng, et al, 2013). As an example, Cheng et al (Cheng, et al, 2000) observed that when isolating bone marrow stromal cells (BMSCs), complexes existed consisting of BMSCs and MKs, demonstrating a physical association between these cells.…”

Section: Introductionmentioning

confidence: 99%

Signaling Pathways Involved in Megakaryocyte‐Mediated Proliferation of Osteoblast Lineage Cells

Cheng

Streicher

Waning

et al. 2014

Journal Cellular Physiology

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Recent studies suggest that megakaryocytes (MKs) may play a significant role in skeletal homeostasis, as evident by the occurrence of osteosclerosis in multiple MK related diseases (Thiele, et al., 1999, Lennert, et al., 1975, Chagraoui, et al., 2006). We previously reported a novel interaction whereby MKs enhanced proliferation of osteoblast lineage/osteoprogenitor cells (OBs) by a mechanism requiring direct cell-cell contact. However, the signal transduction pathways and the downstream effector molecules involved in this process have not been characterized. Here we show that MKs contact with OBs, via beta1 integrin, activate the p38/MAPKAPK2/p90RSK kinase cascade in the bone cells, which causes Mdm2 to neutralizes p53/Rb-mediated check point and allows progression through the G1/S. Interestingly, activation of MAPK (ERK1/2) and AKT, collateral pathways that regulate the cell cycle, remained unchanged with MK stimulation of OBs. The MK-to-OB signaling ultimately results in significant increases in the expression of c-fos and cyclin A, necessary for sustaining the OB proliferation. Overall, our findings show that OBs respond to the presence of MKs, in part, via an integrin-mediated signaling mechanism, activating a novel response axis that de-represses cell cycle activity. Understanding the mechanisms by which MKs enhance OB proliferation will facilitate the development of novel anabolic therapies to treat bone loss associated with osteoporosis and other bone-related diseases.

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“…In addition, work from Boutahar and Sonomura have explored the theory that mechanical stimulation activates Pyk2 signaling in osteoblasts and renal tubular epithelial cells [20, 21]. Furthermore, Pyk2 was identified to affect cell proliferation in several cell types in response to many different stimuli [22, 23]. However, the special functions of Pyk2 in the process of mechanotransduced signal pathways in chondrocytes were completely unknown.…”

Section: Introductionmentioning

confidence: 99%

Periodic Mechanical Stress INDUCES Chondrocyte Proliferation and Matrix Synthesis via CaMKII-Mediated Pyk2 Signaling

Liang

Zeng

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Periodic mechanical stress can promote chondrocyte proliferation and matrix synthesis to improve the quality of tissue-engineered cartilage. Although the integrin β1–ERK1/2 signal cascade has been implicated in periodic mechanical stress-induced mitogenic effects in chondrocytes, the precise mechanisms have not been fully established. The current study was designed to probe the roles of CaMKII and Pyk2 signaling in periodic mechanical stress-mediated chondrocyte proliferation and matrix synthesis. Methods: Chondrocytes were subjected to periodic mechanical stress, proliferation was assessed by direct cell counting and CCK-8 assay; gene expressions were analyzed using quantitative real-time PCR, protein abundance by Western blotting. Results: Mechanical stress, markedly enhanced the phosphorylation levels of Pyk2 at Tyr⁴⁰² and CaMKII at Thr²⁸⁶. Both suppression of Pyk2 with Pyk2 inhibitor PF431396 or Pyk2 shRNA and suppression of CaMKII with CaMKII inhibitor KN-93 or CaMKII shRNA blocked periodic mechanical stress-induced chondrocyte proliferation and matrix synthesis. Additionally, either pretreatment with KN-93 or shRNA targeted to CaMKII prevented the activation of ERK1/2 and Pyk2 under conditions of periodic mechanical stress. Interestingly, in relation to periodic mechanical stress, in the context of Pyk2 inhibition with PF431396 or its targeted shRNA, only the phosphorylation levels of ERK1/2 were abrogated, while CaMKII signal activation was not affected. Moreover, the phosphorylation levels of CaMKII- Thr²⁸⁶ and Pyk2- Tyr⁴⁰² were abolished after pretreatment with blocking antibody against integrinβ1 exposed to periodic mechanical stress. Conclusion: Our results collectively indicate that periodic mechanical stress promotes chondrocyte proliferation and matrix synthesis through the integrinβ1–CaMKII–Pyk2–ERK1/2 signaling cascade.

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Megakaryocytes Regulate Expression of Pyk2 Isoforms and Caspase-mediated Cleavage of Actin in Osteoblasts

Cited by 26 publications

References 64 publications

Osteomacs interact with megakaryocytes and osteoblasts to regulate murine hematopoietic stem cell function

Osteomacs interact with megakaryocytes and osteoblasts to regulate murine hematopoietic stem cell function

Signaling Pathways Involved in Megakaryocyte‐Mediated Proliferation of Osteoblast Lineage Cells

Periodic Mechanical Stress INDUCES Chondrocyte Proliferation and Matrix Synthesis via CaMKII-Mediated Pyk2 Signaling

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