Pigment Epithelium Derived Factor (PEDF) Induces Osteogenic Properties in Skeletal Myocytes: PEDF Upregulates Osteogenic Markers and Enhances Mineralisation Mediated By 1/2Erk MAPK Signalling in Skeletal Myocytes

Presentation Number: SAT 346
Date of Presentation: April 1st, 2017

Revathy Carnagarin*1, Arun M Dharmarajan2 and Crispin Dass3
1Curtin University, Perth, AUSTRALIA, 2Curtin University, Perth, WA, Australia, 3Curtin University, Perth, Australia

Abstract

Pigment epithelium derived factor induces osteogenic properties in skeletal myocytes: PEDF upregulates osteogenic markers and enhances mineralisation mediated by 1/2Erk MAPK signalling in skeletal myocytes.

Revathy Carnagarina,b,c, , Arun M. Dharmarajana,c, Crispin R. Dassa,b

aCurtin Health Innovation Research Institute, Bentley 6102, Australia

bSchool of Pharmacy, Curtin University, Bentley 6102, Australia

cSchool of Biomedical Sciences, Curtin University, Bentley 6102, Australia

 

Bone regeneration is a complex physiological process that is currently addressed by a plethora of different strategies and autologous bone grafting continues to remain the gold standard. However, massive defects arising from skeletal abnormalities post trauma, infection and tumour resection necessitates the identification of further strategies in the form tissue engineering, gene therapy and potent osteo-inductive agents that could enhance the bone repair process. PEDF has a signatory effect on osteogenesis. PEDF gene defect results in osteogenesis imperfecta IV characterised by bone mineralisation defects and PEDF restoration improved bone mineralisation in murine models of osteogenesis imperfecta VI and normalised mineralisation defects in pluripotent stem cells derived from PEDF null patients [Belinsky et al 2016]. PEDF regulates the expression of osteoblastic genes, enhanced mineralisation in murine and human MSCs [Elahy et al 2016] and suppressed inhibitors of bone formation [Li et al 2013, 2015]. Muscle plays a vital role in bone regeneration by contributing satellite cells, muscle stem cells and growth factors and the use of muscle flaps to cover bone defects and prevent infections could be further improvised to support bone healing directly by using a suitable osteokine such as PEDF.

To study the potency of PEDF in this perspective, we analysed PEDF-treated mice and human skeletal myoblasts for osteogenic properties. PEDF treatment of skeletal myoblasts at a physiological concentration of 100nM induced the expression of osteogenic markers such as osteocalcin and alkaline phosphatase. PEDF activated Erk1/2 MAPK signalling which governed the expression of osteogenic markers and mineralisation. Additional analysis demonstrated PEDF as a potent osteogenic signal that induced osteogenesis independent of osteogenic supplements to convert the C2C12 myogenic differentiation pathway into osteoblast lineage. PEDF also enhanced mineral deposition in human primary muscle myoblasts. These effects of PEDF were tested in vivo using Balbc mice. This study provides new insights into the signalling and molecular aspects of PEDF to modulate the differentiation commitment of skeletal myocytes, and we speculate that this could pave the way for new strategies that could overcome the limitations of existing therapies to accelerate bone regeneration, or even to address skeletal disorders.

 

Nothing to Disclose: RC, AMD, CD