HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Novel oxysterols have pro-osteogenic and anti-adipogenic effects in vitro and induce spinal fusion in vivo.

Abstract
Stimulation of bone formation by osteoinductive materials is of great clinical importance in spinal fusion surgery, repair of bone fractures, and in the treatment of osteoporosis. We previously reported that specific naturally occurring oxysterols including 20(S)-hydroxycholesterol (20S) induce the osteogenic differentiation of pluripotent mesenchymal cells, while inhibiting their adipogenic differentiation. Here we report the characterization of two structural analogues of 20S, Oxy34 and Oxy49, which induce the osteogenic and inhibit the adipogenic differentiation of bone marrow stromal cells (MSC) through activation of Hedgehog (Hh) signaling. Treatment of M2-10B4 MSC with Oxy34 or Oxy49 induced the expression of osteogenic differentiation markers Runx2, Osterix (Osx), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN), as well as ALP enzymatic activity and robust mineralization. Treatment with oxysterols together with PPARĪ³ activator, troglitazone (Tro), inhibited mRNA expression for adipogenic genes PPARĪ³, LPL, and aP2, and inhibited the formation of adipocytes. Efficacy of Oxy34 and Oxy49 in stimulating bone formation in vivo was assessed using the posterolateral intertransverse process rat spinal fusion model. Rats receiving collagen implants with Oxy 34 or Oxy49 showed comparable osteogenic efficacy to BMP2/collagen implants as measured by radiography, MicroCT, and manual inspection. Histological analysis showed trabecular and cortical bone formation by oxysterols and rhBMP2 within the fusion mass, with robust adipogenesis in BMP2-induced bone and significantly less adipocytes in oxysterol-induced bone. These data suggest that Oxy34 and Oxy49 are effective novel osteoinductive molecules and may be suitable candidates for further development and use in orthopedic indications requiring local bone formation.
AuthorsJared S Johnson, Vicente Meliton, Woo Kyun Kim, Kwang-Bok Lee, Jeffrey C Wang, Khanhlinh Nguyen, Dongwon Yoo, Michael E Jung, Elisa Atti, Sotirios Tetradis, Renata C Pereira, Clara Magyar, Taya Nargizyan, Theodore J Hahn, Francine Farouz, Scott Thies, Farhad Parhami
JournalJournal of cellular biochemistry (J Cell Biochem) Vol. 112 Issue 6 Pg. 1673-84 (Jun 2011) ISSN: 1097-4644 [Electronic] United States
PMID21503957 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Wiley-Liss, Inc.
Chemical References
  • Hydroxycholesterols
  • Alkaline Phosphatase
Topics
  • Adipogenesis (drug effects)
  • Alkaline Phosphatase (metabolism)
  • Animals
  • Bone Marrow Cells (cytology, drug effects)
  • Cell Differentiation (drug effects)
  • Cell Line
  • Hydroxycholesterols (pharmacology)
  • Male
  • Mice
  • Osteogenesis (drug effects)
  • Radiography
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spinal Fusion
  • Spine (cytology, diagnostic imaging, drug effects)
  • Stromal Cells (cytology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: