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Ajulemic Acid, a Nonpsychoactive Cannabinoid Acid, Suppresses Osteoclastogenesis in Mononuclear Precursor Cells and Induces Apoptosis in Mature Osteoclast-Like Cells

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Ajulemic Acid, a Nonpsychoactive Cannabinoid Acid, Suppresses Osteoclastogenesis in Mononuclear Precursor Cells and Induces Apoptosis in Mature Osteoclast-Like Cells Project Code: JXR 5906 Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononuclear precursor cells and induces apoptosis in mature osteoclast-like cells. A Major Qualifying Project Report submitted to the Faculty of WORCESTER POLYTECHNIC INSTITUTE in partial fulfillment of the requirements for the Degree of Bachelor of Science By: ________________________ Kerri L. George Date: 2 March 2007 Advisor: Jill Rulfs, Professor Co-advisors: Dr. Jane Lian and Dr. Robert Zurier i Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononuclear precursor cells and induces apoptosis in mature osteoclast-like cells. Kerri L. George, Laura Saltman, Gary Stein, Jane Lian, and Robert Zurier Departments of Medicine (KL.G and R.B.Z..) and Cell Biology (L.S,G.S., and J.L.), University of Massachusetts Medical School, Worcester, Massachusetts ABSTRACT Ajulemic acid (AjA) is a synthetic analog of the tetrahydrocannabinol (THC) metabolite THC-11-oic acid. AjA reduces release of the inflammatory cytokine interleukin-1β (IL-1β) from peripheral blood and synovial fluid monocytes, and prevents bone degradation in a rat model of inflammatory arthritis. Because preosteoclasts are of monocyte lineage, we initiated these studies to understand the direct effects of AjA on both osteoclast differentiation and activity. In this paper, we demonstrate that AjA suppresses osteoclastogenesis in vitro in a concentration dependent manner. INTRODUCTION Osteoclasts, responsible for bone resorption, are large multinucleated cells formed by fusion of hematopoietic precursor cells of the monocyte/macrophage family. Osteoclasts usually have between 10 and 20 nuclei per cell but may have as many as 100 (Roodman, 1996). They are formed continuously throughout life under normal physiological conditions to maintain calcium homeostasis and to support normal bone remodeling. In response to hormones and mechanical stimuli, the mononuclear hematopoietic lineage cells fuse to form the differentiated osteoclast (Saltman, 2005). During osteoclast differentiation, signature phenotypic markers are expressed including tartrate-resistant acid phosphatase (TRAP), the calcitonin receptor, matrix 2 metalloproteinase 9 (MMP-9), and cathepsin K (Suda, 1999; Vaananen and Zhao, 2002; Boyle, 2003; Teitelbaum and Ross, 2003; Saltman, 2005). The discovery that receptor activator of NF-kB ligand (RANKL) is the major physiological mediator of osteoclast differentiation enabled investigators to generate pure populations of osteoclasts in vitro from the mononuclear phagocyte precursor (Lacey, 1998; Yasuda, 1998). This major breakthrough led to a greater understanding of the mechanisms controlling osteoclast differentiation and activity under normal biological and pathological conditions (Boyle, 2003; Teitelbaum and Ross, 2003; Saltman, 2005). A murine macrophage cell line, RAW264.7, can differentiate readily into osteoclast-like cells in the presence of RANKL (Hsu, 1999). Known markers of osteoclasts are induced in the multinuclear TRAP-positive cells that form from the RAW264.7 cells, confirmation that these cells possess major characteristics of osteoclasts (Hotokezata, 2002). RANK signaling pathways driven by RANKL, are controlled at several levels resulting in enhanced or reduced osteoclastogenesis. Activation of osteoclast surface receptors for IL-1, c- Fms proto-oncogene, tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2), and T-cell growth factor beta (TGF-β) potentiate osteoclastogenesis in vitro, and can stimulate bone resorption in vivo (Boyle, 2003). The Cannabis plant has been a source of medicinal preparations since the earliest written records on pharmacobotany. A major obstacle to broad acceptance of cannabinoids as therapeutic agents is their potent psychoactive effects. A class of cannabinoids, the carboxyl tetrahydrocannabinols, which are metabolites of tetrahydrocannabinol (THC), shows promise as therapeutic agents that are free of cannabimimetic central nervous system activity (Burstein, 1972). These compounds, called cannabinoid acids, include all the carboxylic acid metabolites of 3 the cannabinoids and their synthetic analogs. One analog, 1’1’-dimethylheptyl-THC-11-oic acid, termed ajulemic acid (AjA), is a potent antiinflammatory and analgesic agent in several animal models (Dajani, 1999). In addition, AjA is not psychoactive in mice. In fact, AjA suppresses THC-induced catalepsy in mice (Burstein, 1999). AjA, given to rats orally, reduces significantly the severity of adjuvant-induced polyarthritis in rats. Histomorphological evaluation of the joints suggested that synovial inflammation occurred in treated animals, but that it did not progress to cartilage degradation, bone erosion, and distortion of joint architecture, as was observed in rats given placebo (Zurier, 1998). Results of experiments presented in this paper indicate that AjA suppresses osteoclastogenesis in vitro. Many adult skeletal diseases are due to excess osteoclastic activity, leading to an imbalance in bone remodeling which favors resorption (Rodan, 2000). These include osteoporosis, periodontal disease, rheumatoid arthritis, multiple myeloma, and metastatic cancers (Boyle, 2003). For individuals with osteoporosis, bone fractures can represent life-threatening events, and today in excess of 70 million people worldwide are at risk (Boyle, 2003). In an initial examination of the effects of AjA on osteoclasts, we observed that addition to mononuclear precursors suppressed osteoclastogenesis and also reduced cell number. In an investigation of the observed reduced cell number, we discovered that AjA induced apoptosis of osteoclasts. Apoptosis is recognized as a mode of cell death in which cells are deleted in the midst of living tissue (Kerr, 1972). Apoptotic cells express characteristic features such as cell shrinkage, nuclear condensation, loss of membrane microvilli, and surface blebbing (Wyllie, 1984). Fragments of apoptotic cells are digested by resident phagocytes without influx of inflammatory cells (Polunovsky, 1993). Thus, in contrast to cell death by necrosis, apoptosis is regulated and has been termed “programmed cell death” (Cohen, 1993). It is possible that the effects of AjA on 4 osteoclastogenesis and on osteoclast cell number will have a protective effect in diseases such as osteoporosis and rheumatoid arthritis characterized by excess osteoclast activity. MATERIALS AND METHODS AjA was obtained from Organix (Woburn, MA). Its purity was monitored on high- pressure liquid chromatography by comparison with material synthesized previously (Burstein, 1992). The sample was 97% chemically pure, and was >99% chirally pure in the enatiomer. Establishment of Osteoclast Cultures. RAW264.7 cells were thawed and transferred to100mm plates (Corning, Corning, NY), and cultured 6-7 days in DMEM medium supplemented with 10% FBS, 2mM L-glutamine and 1% (v/v) penicillin-streptomycin (R&D Systems, Minneapolis, MN). To induce RAW264.7 cells to differentiate into osteoclasts, bacterially-produced recombinant RANKL (5ng/ml) was added. RAW264.7 cells were plated at the density of 2X105/plate when no RANKL was added, and 4X105/plate when RANKL was added. Osteoclast staining. Osteoclast formation was monitored cytochemically by staining for tartrate-resistant acid phosphatase (TRAP). TRAP is regarded as an osteoclast marker and is mostly characterized by its biochemical property, i.e., through its acid phosphatase function, which cannot block tartrate (Filgueira, 2004). A histochemical method, commercially available as a kit by Sigma Diagnostics (St Louis, MO), is widely used and has proved to be the standard method for specific detection of osteoclasts. After TRAP staining, the numbers of osteoclasts (with ≥3 nuclei) were quantified by counting in 3 different fields. RNA Isolation and real-time PCR. Total cellular RNA was isolated using Trizol reagent (Invitrogen Life Technologies, Carlsbad, CA) as per manufacturer’s directions and 5 resuspended in DEPC-treated water. For RT-PCR, RNA was treated with DNase I and purified using a DNA-freeRNAkit (Zymo Research, Orange, CA). cDNA was synthesized using the Invitrogen SuperScript First Strand Synthesis System with oligo dT primers. GAPDH, BAX, BCL2, and Histone H4b mRNA were amplified using iTaq SYBR green supermix (Bio-Rad Laboratories, Hercules, CA) and 2.5 pmoles of each primer (Applied Biosystems, Foster City, CA). Conditions for all PCR reactions were as follows: 50°C for 2 min, 95°Cfor 10 min, followed by 40 cycles of 95°C for 15 sec, and 60°C for 1 min. Primers and probes for the TRAP, RANK receptor, cathepsin K, and MMP9 genes were all Assays-on-Demand products from Applied Biosystems and reactions were set up according to the manufacturer’s directions. Real time PCR was performed in triplicate in 25 ml reactions on the ABI Prism 7000 Sequence Detection System. (Saltman, 2005) The relative level of each mRNA was determined using the comparative CT method for relative quantitation using GAPDH as an endogenous reference (Livak and Schmittgen, 2001). Cell Growth. RAW264.7 cells (1X106) were plated and allowed to settle for 2 days. AjA was added to the media on the third day. Cells were scraped, pelleted, and resuspended in 1mL of PBS on each of the three days of AjA treatment. Cells were then counted in a standard hemocytometer. Annexin V Staining for Apoptosis. Phosphatidyl serine (PS) is located in the inner leaflet of the plasma membrane. Early in the apoptotic process, reorganization
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