Cannabinoid receptor type 1 protects against age-related bone loss by regulating osteoblast and adipocyte differentiation of bone marrow stromal cells

Idris, A.I., Sophocleous, A., Landao-Bassonga, E., Merkouris, M., Milligan, G., Baker, D., van't Hof, R.J. and Ralston, S.H. (2009) Cannabinoid receptor type 1 protects against age-related bone loss by regulating osteoblast and adipocyte differentiation of bone marrow stromal cells. Bone, 44(Supple), S222. (doi: 10.1016/j.bone.2009.03.067)

Abstract

Osteoporosis is characterised by reduced bone formation with replacement of the bone marrow compartment by fat, due to an age-dependent reduction in osteoblast differentiation and a reciprocal increase in adipocyte differentiation. Here we report that the type 1 cannabinoid receptor (CB1) regulates this process to protect against age related bone loss. Mice with CB1 deficiency (CB1<sp>-/-</sp>) had a increased peak bone mass when compared with wild type littermates (females; 28% increase and males 14% increase) due to a reduction in bone resorption. However, CB1<sp>-/-</sp> mice developed an accelerated age-related osteoporosis characterised by reduced bone formation and a dramatic accumulation of fat in the bone marrow (BM) compartment. Studies <i>in vitro</i> showed that bone nodule formation was reduced by 45% in marrow stromal cells from CB1<sp>-/-</sp> mice when compared with wild type littermates (p<0.05) and expression of Runx2, alkaline phosphatase and osteopontin were reduced. Conversely, adipocyte differentiation was increased by 30% (p<0.02) in marrow stromal cultures from CB1<sp>-/-</sp> mice when compared with wild type. Adipocyte cultures from CB1<sp>-/-</sp> mice showed enhanced insulin-induced AKT activation and increased expression of the adipocyte-specific genes PPAR gamma and C/EBP when compared with wild type. Adipocyte differentiation was increased in wild type BM cultures exposed to the CB1 selective antagonist AM251, but these effects were blocked by the cannabinoid receptor agonist CP55,490 and the Gi/o inhibitor pertussis toxin, consistent with a CB1 mediated effect. Intracellular cAMP levels were elevated in stromal cells cultured from CB1<sp>-/-</sp> mice and these cells exhibited increased enhanced phosphorylation of the cAMP response element transcription factor CREB. The CB agonist CP55,490 inhibited cAMP accumulation in 3T3-L1 pre-adipocytes and this effect was reversed by AM251 and pertussis toxin. Furthermore, exposure of wild type stromal cells to AM251 was sufficient to stimulate adipogenesis in the absence of the phosphodiesterase inhibitor IBMX. Taken together, these observations indicate that CB1 regulates the commitment of mesenchymal stem cells to differentiate into osteoblasts and adipocytes by a cAMP mediated mechanism. The CB1 pathway therefore plays a unique role in bone metabolism by restraining peak bone mass through effects on osteoclast differentiation but by protecting against age-related bone loss by regulating adipocyte and osteoblast differentiation.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Milligan, Professor Graeme
• Authors: Idris, A.I., Sophocleous, A., Landao-Bassonga, E., Merkouris, M., Milligan, G., Baker, D., van't Hof, R.J., and Ralston, S.H.
• Subjects: Q Science > QH Natural history > QH345 Biochemistry; Q Science > QH Natural history > QH301 Biology
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Bone
• ISSN: 8756-3282