The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts

Su Huang, Pierre P. Eleniste, Kornchanok Wayakanon, Prashant Mandela, Betty A. Eipper, Richard E. Mains, Matthew Allen, Angela Bruzzaniti

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Bone homeostasis is maintained by the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Dysregulation in the activity of the bone cells can lead to osteoporosis, a disease characterized by low bone mass and an increase in bone fragility and risk of fracture. Kalirin is a novel GTP-exchange factor protein that has been shown to play a role in cytoskeletal remodeling and dendritic spine formation in neurons. We examined Kalirin expression in skeletal tissue and found that it was expressed in osteoclasts and osteoblasts. Furthermore, micro-CT analyses of the distal femur of global Kalirin knockout (Kal-KO) mice revealed significantly reduced trabecular and cortical bone parameters in Kal-KO mice, compared to WT mice, with significantly reduced bone mass in 8, 14 and 36. week-old female Kal-KO mice. Male mice also exhibited a decrease in bone parameters but not to the level seen in female mice. Histomorphometric analyses also revealed decreased bone formation rate in 14. week-old female Kal-KO mice, as well as decreased osteoblast number/bone surface and increased osteoclast surface/bone surface. Consistent with our in vivo findings, the bone resorbing activity and differentiation of Kal-KO osteoclasts was increased in vitro. Although alkaline phosphatase activity by Kal-KO osteoblasts was increased in vitro, Kal-KO osteoblasts showed decreased mineralizing activity, as well as decreased secretion of OPG, which was inversely correlated with ERK activity. Taken together, our findings suggest that deletion of Kalirin directly affects osteoclast and osteoblast activity, leading to decreased OPG secretion by osteoblasts which is likely to alter the RANKL/OPG ratio and promote osteoclastogenesis. Therefore, Kalirin may play a role in paracrine and/or endocrine signaling events that control skeletal bone remodeling and the maintenance of bone mass.

Original languageEnglish
Pages (from-to)235-245
Number of pages11
JournalBone
Volume60
DOIs
StatePublished - Mar 2014

Fingerprint

Osteoclasts
Osteoblasts
Bone and Bones
Knockout Mice
Osteogenesis
Dendritic Spines
Bone Remodeling
Bone Resorption
Guanosine Triphosphate
Femur
Osteoporosis
Alkaline Phosphatase
Homeostasis
Maintenance
Neurons

Keywords

  • GTP-exchange factor
  • Osteoprotegerin, bone remodeling
  • Receptor activator of nuclear factor κb ligand

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

Huang, S., Eleniste, P. P., Wayakanon, K., Mandela, P., Eipper, B. A., Mains, R. E., ... Bruzzaniti, A. (2014). The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts. Bone, 60, 235-245. https://doi.org/10.1016/j.bone.2013.12.023

The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts. / Huang, Su; Eleniste, Pierre P.; Wayakanon, Kornchanok; Mandela, Prashant; Eipper, Betty A.; Mains, Richard E.; Allen, Matthew; Bruzzaniti, Angela.

In: Bone, Vol. 60, 03.2014, p. 235-245.

Research output: Contribution to journalArticle

Huang, S, Eleniste, PP, Wayakanon, K, Mandela, P, Eipper, BA, Mains, RE, Allen, M & Bruzzaniti, A 2014, 'The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts', Bone, vol. 60, pp. 235-245. https://doi.org/10.1016/j.bone.2013.12.023
Huang S, Eleniste PP, Wayakanon K, Mandela P, Eipper BA, Mains RE et al. The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts. Bone. 2014 Mar;60:235-245. https://doi.org/10.1016/j.bone.2013.12.023
Huang, Su ; Eleniste, Pierre P. ; Wayakanon, Kornchanok ; Mandela, Prashant ; Eipper, Betty A. ; Mains, Richard E. ; Allen, Matthew ; Bruzzaniti, Angela. / The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts. In: Bone. 2014 ; Vol. 60. pp. 235-245.
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abstract = "Bone homeostasis is maintained by the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Dysregulation in the activity of the bone cells can lead to osteoporosis, a disease characterized by low bone mass and an increase in bone fragility and risk of fracture. Kalirin is a novel GTP-exchange factor protein that has been shown to play a role in cytoskeletal remodeling and dendritic spine formation in neurons. We examined Kalirin expression in skeletal tissue and found that it was expressed in osteoclasts and osteoblasts. Furthermore, micro-CT analyses of the distal femur of global Kalirin knockout (Kal-KO) mice revealed significantly reduced trabecular and cortical bone parameters in Kal-KO mice, compared to WT mice, with significantly reduced bone mass in 8, 14 and 36. week-old female Kal-KO mice. Male mice also exhibited a decrease in bone parameters but not to the level seen in female mice. Histomorphometric analyses also revealed decreased bone formation rate in 14. week-old female Kal-KO mice, as well as decreased osteoblast number/bone surface and increased osteoclast surface/bone surface. Consistent with our in vivo findings, the bone resorbing activity and differentiation of Kal-KO osteoclasts was increased in vitro. Although alkaline phosphatase activity by Kal-KO osteoblasts was increased in vitro, Kal-KO osteoblasts showed decreased mineralizing activity, as well as decreased secretion of OPG, which was inversely correlated with ERK activity. Taken together, our findings suggest that deletion of Kalirin directly affects osteoclast and osteoblast activity, leading to decreased OPG secretion by osteoblasts which is likely to alter the RANKL/OPG ratio and promote osteoclastogenesis. Therefore, Kalirin may play a role in paracrine and/or endocrine signaling events that control skeletal bone remodeling and the maintenance of bone mass.",
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AB - Bone homeostasis is maintained by the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Dysregulation in the activity of the bone cells can lead to osteoporosis, a disease characterized by low bone mass and an increase in bone fragility and risk of fracture. Kalirin is a novel GTP-exchange factor protein that has been shown to play a role in cytoskeletal remodeling and dendritic spine formation in neurons. We examined Kalirin expression in skeletal tissue and found that it was expressed in osteoclasts and osteoblasts. Furthermore, micro-CT analyses of the distal femur of global Kalirin knockout (Kal-KO) mice revealed significantly reduced trabecular and cortical bone parameters in Kal-KO mice, compared to WT mice, with significantly reduced bone mass in 8, 14 and 36. week-old female Kal-KO mice. Male mice also exhibited a decrease in bone parameters but not to the level seen in female mice. Histomorphometric analyses also revealed decreased bone formation rate in 14. week-old female Kal-KO mice, as well as decreased osteoblast number/bone surface and increased osteoclast surface/bone surface. Consistent with our in vivo findings, the bone resorbing activity and differentiation of Kal-KO osteoclasts was increased in vitro. Although alkaline phosphatase activity by Kal-KO osteoblasts was increased in vitro, Kal-KO osteoblasts showed decreased mineralizing activity, as well as decreased secretion of OPG, which was inversely correlated with ERK activity. Taken together, our findings suggest that deletion of Kalirin directly affects osteoclast and osteoblast activity, leading to decreased OPG secretion by osteoblasts which is likely to alter the RANKL/OPG ratio and promote osteoclastogenesis. Therefore, Kalirin may play a role in paracrine and/or endocrine signaling events that control skeletal bone remodeling and the maintenance of bone mass.

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