Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononuclear precursor cells and induces apoptosis in mature osteoclast-like cells

Authors

  • Kerri L. George,

    1. Department of Medicine, Division of Rheumatology, University of Massachusetts Medical School, Worcester Massachusetts 01655
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  • Laura H. Saltman,

    1. Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester Massachusetts 01655
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  • Gary S. Stein,

    1. Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester Massachusetts 01655
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  • Jane B. Lian,

    1. Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester Massachusetts 01655
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  • Robert B. Zurier

    Corresponding author
    1. Department of Medicine, Division of Rheumatology, University of Massachusetts Medical School, Worcester Massachusetts 01655
    • Department of Medicine, Division of Rheumatology, 55 Lake Avenue North, University of Massachusetts Medical School, Worcester, MA 01655.
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  • Kerri L. George and Laura H. Saltman shared first authorship.

  • Kerri L. George in partial fulfillment for the Major Qualifying Project for the BS in Biochemistry at Worcester Polytechnic Institute.

Abstract

Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, prevents joint tissue injury in rats with adjuvant induced arthritis. Because activation of osteoclasts is central to the pathogenesis of bone erosion in patients with rheumatoid arthritis (RA), we investigated the influence of AjA on osteoclast differentiation and survival. Osteoclast cultures were established by stimulation of RAW264.7 cells and primary mouse bone marrow cultures with receptor activator of NF-κB ligand (RANKL). Simultaneous addition of AjA (15 and 30 µM) and RANKL to both culture systems significantly suppressed development of multinucleated osteoclasts (osteoclastogenesis) in a dose dependent manner, as determined by quantification of multinuclear, tartrate-resistant acid phosphatase (TRAP)-positive cells. AjA impaired growth of RAW264.7 monocytes and prevented further osteoclast formation in cultures in which osteoclastogenesis had already begun. Reduction by AjA of both monocyte growth and osteoclast formation was associated with apoptosis, assayed by annexin V and propidium iodide staining, and caspase activity. The anti-osteoclastogenic effects of AjA did not require the continuous presence of AjA in the cell cultures. Based on these findings, we propose that AjA or other nonpsychoactive synthetic analogs of Cannabis constituents may be useful therapy for diseases such as RA and osteoporosis in which bone resorption is a central feature. J. Cell. Physiol. 214: 714–720, 2008. © 2007 Wiley-Liss, Inc.

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