Lnk Deficiency Leads to TPO-Mediated Osteoclastogenesis and Increased Bone Mass Phenotype

David J. Olivos, Marta Alvarez, Ying Hua Cheng, Richard Adam Hooker, Wendy A. Ciovacco, Monique Bethel, Haley Mcgough, Christopher Yim, Brahmananda R. Chitteti, Pierre P. Eleniste, Mark C. Horowitz, Edward Srour, Angela Bruzzaniti, Robyn K. Fuchs, Melissa Kacena

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The Lnk adapter protein negatively regulates the signaling of thrombopoietin (TPO), the main megakaryocyte (MK) growth factor. Lnk-deficient (-/-) mice have increased TPO signaling and increased MK number. Interestingly, several mouse models exist in which increased MK number leads to a high bone mass phenotype. Here we report the bone phenotype of these mice. MicroCT and static histomorphometric analyses at 20 weeks showed the distal femur of Lnk-/- mice to have significantly higher bone volume fraction and trabecular number compared to wild-type (WT) mice. Notably, despite a significant increase in the number of osteoclasts (OC), and decreased bone formation rate in Lnk-/- mice compared to WT mice, Lnk-/- mice demonstrated a 2.5-fold greater BV/TV suggesting impaired OC function in vivo. Additionally, Lnk-/- mouse femurs exhibited non-significant increases in mid-shaft cross-sectional area, yet increased periosteal BFR compared to WT femurs was observed. Lnk-/- femurs also had non-significant increases in polar moment of inertia and decreased cortical bone area and thickness, resulting in reduced bone stiffness, modulus, and strength compared to WT femurs. Of note, Lnk is expressed by OC lineage cells and when Lnk-/- OC progenitors are cultured in the presence of TPO, significantly more OC are observed than in WT cultures. Lnk is also expressed in osteoblast (OB) cells and in vitro reduced alkaline phosphatase activity was observed in Lnk-/- cultures. These data suggest that both direct effects on OB and OC as well as indirect effects of MK in regulating OB contributes to the observed high bone mass.

Original languageEnglish (US)
JournalJournal of Cellular Biochemistry
DOIs
StateAccepted/In press - 2017

Fingerprint

Thrombopoietin
Osteogenesis
Bone
Osteoclasts
Bone and Bones
Megakaryocytes
Femur
Osteoblasts
MASS syndrome
X-Ray Microtomography
Cell culture
Alkaline Phosphatase
Volume fraction
Intercellular Signaling Peptides and Proteins
Stiffness
Phenotype

Keywords

  • BONE MASS
  • BONE PHENOTYPE
  • LNK
  • MEGAKARYOCYTES
  • OSTEOBLASTS
  • OSTEOCLASTS

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lnk Deficiency Leads to TPO-Mediated Osteoclastogenesis and Increased Bone Mass Phenotype. / Olivos, David J.; Alvarez, Marta; Cheng, Ying Hua; Hooker, Richard Adam; Ciovacco, Wendy A.; Bethel, Monique; Mcgough, Haley; Yim, Christopher; Chitteti, Brahmananda R.; Eleniste, Pierre P.; Horowitz, Mark C.; Srour, Edward; Bruzzaniti, Angela; Fuchs, Robyn K.; Kacena, Melissa.

In: Journal of Cellular Biochemistry, 2017.

Research output: Contribution to journalArticle

Olivos, DJ, Alvarez, M, Cheng, YH, Hooker, RA, Ciovacco, WA, Bethel, M, Mcgough, H, Yim, C, Chitteti, BR, Eleniste, PP, Horowitz, MC, Srour, E, Bruzzaniti, A, Fuchs, RK & Kacena, M 2017, 'Lnk Deficiency Leads to TPO-Mediated Osteoclastogenesis and Increased Bone Mass Phenotype', Journal of Cellular Biochemistry. https://doi.org/10.1002/jcb.25874
Olivos, David J. ; Alvarez, Marta ; Cheng, Ying Hua ; Hooker, Richard Adam ; Ciovacco, Wendy A. ; Bethel, Monique ; Mcgough, Haley ; Yim, Christopher ; Chitteti, Brahmananda R. ; Eleniste, Pierre P. ; Horowitz, Mark C. ; Srour, Edward ; Bruzzaniti, Angela ; Fuchs, Robyn K. ; Kacena, Melissa. / Lnk Deficiency Leads to TPO-Mediated Osteoclastogenesis and Increased Bone Mass Phenotype. In: Journal of Cellular Biochemistry. 2017.
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abstract = "The Lnk adapter protein negatively regulates the signaling of thrombopoietin (TPO), the main megakaryocyte (MK) growth factor. Lnk-deficient (-/-) mice have increased TPO signaling and increased MK number. Interestingly, several mouse models exist in which increased MK number leads to a high bone mass phenotype. Here we report the bone phenotype of these mice. MicroCT and static histomorphometric analyses at 20 weeks showed the distal femur of Lnk-/- mice to have significantly higher bone volume fraction and trabecular number compared to wild-type (WT) mice. Notably, despite a significant increase in the number of osteoclasts (OC), and decreased bone formation rate in Lnk-/- mice compared to WT mice, Lnk-/- mice demonstrated a 2.5-fold greater BV/TV suggesting impaired OC function in vivo. Additionally, Lnk-/- mouse femurs exhibited non-significant increases in mid-shaft cross-sectional area, yet increased periosteal BFR compared to WT femurs was observed. Lnk-/- femurs also had non-significant increases in polar moment of inertia and decreased cortical bone area and thickness, resulting in reduced bone stiffness, modulus, and strength compared to WT femurs. Of note, Lnk is expressed by OC lineage cells and when Lnk-/- OC progenitors are cultured in the presence of TPO, significantly more OC are observed than in WT cultures. Lnk is also expressed in osteoblast (OB) cells and in vitro reduced alkaline phosphatase activity was observed in Lnk-/- cultures. These data suggest that both direct effects on OB and OC as well as indirect effects of MK in regulating OB contributes to the observed high bone mass.",
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T1 - Lnk Deficiency Leads to TPO-Mediated Osteoclastogenesis and Increased Bone Mass Phenotype

AU - Olivos, David J.

AU - Alvarez, Marta

AU - Cheng, Ying Hua

AU - Hooker, Richard Adam

AU - Ciovacco, Wendy A.

AU - Bethel, Monique

AU - Mcgough, Haley

AU - Yim, Christopher

AU - Chitteti, Brahmananda R.

AU - Eleniste, Pierre P.

AU - Horowitz, Mark C.

AU - Srour, Edward

AU - Bruzzaniti, Angela

AU - Fuchs, Robyn K.

AU - Kacena, Melissa

PY - 2017

Y1 - 2017

N2 - The Lnk adapter protein negatively regulates the signaling of thrombopoietin (TPO), the main megakaryocyte (MK) growth factor. Lnk-deficient (-/-) mice have increased TPO signaling and increased MK number. Interestingly, several mouse models exist in which increased MK number leads to a high bone mass phenotype. Here we report the bone phenotype of these mice. MicroCT and static histomorphometric analyses at 20 weeks showed the distal femur of Lnk-/- mice to have significantly higher bone volume fraction and trabecular number compared to wild-type (WT) mice. Notably, despite a significant increase in the number of osteoclasts (OC), and decreased bone formation rate in Lnk-/- mice compared to WT mice, Lnk-/- mice demonstrated a 2.5-fold greater BV/TV suggesting impaired OC function in vivo. Additionally, Lnk-/- mouse femurs exhibited non-significant increases in mid-shaft cross-sectional area, yet increased periosteal BFR compared to WT femurs was observed. Lnk-/- femurs also had non-significant increases in polar moment of inertia and decreased cortical bone area and thickness, resulting in reduced bone stiffness, modulus, and strength compared to WT femurs. Of note, Lnk is expressed by OC lineage cells and when Lnk-/- OC progenitors are cultured in the presence of TPO, significantly more OC are observed than in WT cultures. Lnk is also expressed in osteoblast (OB) cells and in vitro reduced alkaline phosphatase activity was observed in Lnk-/- cultures. These data suggest that both direct effects on OB and OC as well as indirect effects of MK in regulating OB contributes to the observed high bone mass.

AB - The Lnk adapter protein negatively regulates the signaling of thrombopoietin (TPO), the main megakaryocyte (MK) growth factor. Lnk-deficient (-/-) mice have increased TPO signaling and increased MK number. Interestingly, several mouse models exist in which increased MK number leads to a high bone mass phenotype. Here we report the bone phenotype of these mice. MicroCT and static histomorphometric analyses at 20 weeks showed the distal femur of Lnk-/- mice to have significantly higher bone volume fraction and trabecular number compared to wild-type (WT) mice. Notably, despite a significant increase in the number of osteoclasts (OC), and decreased bone formation rate in Lnk-/- mice compared to WT mice, Lnk-/- mice demonstrated a 2.5-fold greater BV/TV suggesting impaired OC function in vivo. Additionally, Lnk-/- mouse femurs exhibited non-significant increases in mid-shaft cross-sectional area, yet increased periosteal BFR compared to WT femurs was observed. Lnk-/- femurs also had non-significant increases in polar moment of inertia and decreased cortical bone area and thickness, resulting in reduced bone stiffness, modulus, and strength compared to WT femurs. Of note, Lnk is expressed by OC lineage cells and when Lnk-/- OC progenitors are cultured in the presence of TPO, significantly more OC are observed than in WT cultures. Lnk is also expressed in osteoblast (OB) cells and in vitro reduced alkaline phosphatase activity was observed in Lnk-/- cultures. These data suggest that both direct effects on OB and OC as well as indirect effects of MK in regulating OB contributes to the observed high bone mass.

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