Significant loss of bone due to trauma, underlying metabolic disease, or lack of repair due to old age surpasses the body’s endogenous bone repair mechanisms. Mesenchymal stem cells (MSCs) are adult stem cells which may represent an ideal cell type for use in cell-based tissue engineered bone regeneration strategies. The body’s endocannabinoid system has been identified as a central regulator of bone metabolism. The aim of the study was to elucidate the role of the cannabinoid receptor type 1 in the differentiation and survival of MSCs. We show that the cannabinoid receptor type 1 has a prosurvival function during acute cell stress. Additionally, we show that the phytocannabinoid, -Tetrahydrocannabinol, has a negative impact on MSC survival and osteogenesis. Overall, these results show the potential for the modulation of the cannabinoid system in cell-based tissue engineered bone regeneration strategies whilst highlighting cannabis use as a potential cause for concern in the management of orthopaedic patients. 1. Introduction Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in the bone marrow which can differentiate along several lineages, for example, bone, cartilage, and tendon [1]. Musculoskeletal repair relies on a series of orchestrated events that direct the differentiation of MSCs to its progeny, for example, osteoblasts, chondrocytes, and tenocytes. MSCs represent an ideal cell population for use in tissue engineering and regenerative medicine due to their ease of isolation, multipotency, lack of immunogenicity, and immunosuppressive effects [2]. Tissue engineering aims to learn how to induce, modulate and control the differentiation process of MSCs in order to provide therapeutics for musculoskeletal diseases [3]. We have recently shown that the osteogenic and chondrogenic differentiation process may be controlled by specific growth factors [4], hypoxia [5], and biophysical stimulation [6]. The endocannabinoid system is comprised of two G protein-coupled receptors, CB1 and CB2, the endogenous ligands anandamide and 2-arachidonoylglycerol, and their degradative enzymes fatty acid amide hydrolase and monoacylglycerol lipase, respectively. In addition, exogenous cannabinoids such as the bioactive lipids isolated from the Cannabis sativa plant and synthetic cannabinoids are currently used therapeutically for a number of diseases such as multiple sclerosis [7]. However, phytocannabinoids have a dual toxicity profile with the psychoactive component of cannabis, Δ9-Tetrahydrocannabinol (Δ9-THC), inducing cell death in a number of
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