Bone Cell Biology

Introduction

The research program on bone cell biology is jointly led by Dr Rob Van't Hof and Professor Stuart Ralston, focussing on the role of nitric oxide and the endocannabinoids as regulators of bone remodelling.

Nitric oxide is a free-radical which plays a role in many physiological processes such as cardiovascular homeostasis and neurotransmission. Over the past decade however, increasing interest has focussed on the role that nitric oxide plays in regulating bone cell activity in vitro and bone mass in vivo (reviewed by Van't Hof & Ralston, Immunology, 2001). Nitric oxide is synthesised by one of three nitric oxide synthase isoforms, and it is of interest that these different isoforms subserve differing functions in the skeleton. For example, the inducible isoform of nitric oxide synthase (iNOS) mediates some of the effects of pro-inflammatory cytokines on bone and is essential for IL-1 induced bone resorption (Van't Hof et al. Proc Natl Acad Sci, USA). In contrast, the endothelial (eNOS) isoform is essential for normal osteoblast function and for mediating the anabolic effects of oestrogen on the skeleton (Armour et al, Endocrinology 2001). The neuronal isoform of nitric oxide synthase (nNOS) is mainly expressed in the central nervous system and is present at very low levels in bone tissue. Despite this nNOS plays a key role in regulating bone mass and bone turnover, raising the possibility that it does so through a neurogenic pathway (Van't Hof et al. Endocrinology 2004). Ongoing research within the unit funded by the ARC and the Wellcome trust seeks to investigate the mechanisms by which these different NOS isoforms affect the skeleton.

Research on the role of the endocannabinoid system in bone is led by Professor Stuart Ralston. The endocannabinoid system plays a role in regulating a variety of physiological processes such as appetite, pain, and immune responses. Endogenously produced cannabinoids are hydrophobic molecules derived from hydrolysis of membrane phospholipids that interact with the type 1 (CB1) and 2 (CB2) cannabinoid receptors and the GPR55 receptor to regulate bone cell function through a variety of signaling pathways. Our research has shown that the CB1 receptor plays a key role in regulating osteoclast function and bone mass since deficiency of CB1 or pharmacological inhibitors of CB1 prevent bone loss by inhibiting bone resorption (Idris et al Nature Medicine 2005;11:774-779). Remarkably however the CB1 also regulates bone formation and protects against age-related osteoporosis by regulating differentiation of bone marrow stem cells into osteoblasts and adipocytes (Idris et al. Cell Metabolism 2009;10:139-147). The CB2 receptor also seems to protect against bone loss since CB2 deficiency can lead to osteoporosis but this is only apparent with increasing age (Ofek et al PNAS 2006;103:696-701) The GPR55 receptor has recently been shown to play a role in regulating bone resorption (Whyte et al PNAS 2009;106:16511-16516). So far most of the research on cannabinoids and bone has involved experimental models, but clinical studies are now being initiated to determine whether recreational use of cannabis has positive or negative effects on the skeleton.

	Introduction Contact	Bone Cell Biology Introduction The research program on bone cell biology is jointly led by Dr Rob Van't Hof and Professor Stuart Ralston, focussing on the role of nitric oxide and the endocannabinoids as regulators of bone remodelling. Nitric oxide is a free-radical which plays a role in many physiological processes such as cardiovascular homeostasis and neurotransmission. Over the past decade however, increasing interest has focussed on the role that nitric oxide plays in regulating bone cell activity in vitro and bone mass in vivo (reviewed by Van't Hof & Ralston, Immunology, 2001). Nitric oxide is synthesised by one of three nitric oxide synthase isoforms, and it is of interest that these different isoforms subserve differing functions in the skeleton. For example, the inducible isoform of nitric oxide synthase (iNOS) mediates some of the effects of pro-inflammatory cytokines on bone and is essential for IL-1 induced bone resorption (Van't Hof et al. Proc Natl Acad Sci, USA). In contrast, the endothelial (eNOS) isoform is essential for normal osteoblast function and for mediating the anabolic effects of oestrogen on the skeleton (Armour et al, Endocrinology 2001). The neuronal isoform of nitric oxide synthase (nNOS) is mainly expressed in the central nervous system and is present at very low levels in bone tissue. Despite this nNOS plays a key role in regulating bone mass and bone turnover, raising the possibility that it does so through a neurogenic pathway (Van't Hof et al. Endocrinology 2004). Ongoing research within the unit funded by the ARC and the Wellcome trust seeks to investigate the mechanisms by which these different NOS isoforms affect the skeleton. Research on the role of the endocannabinoid system in bone is led by Professor Stuart Ralston. The endocannabinoid system plays a role in regulating a variety of physiological processes such as appetite, pain, and immune responses. Endogenously produced cannabinoids are hydrophobic molecules derived from hydrolysis of membrane phospholipids that interact with the type 1 (CB1) and 2 (CB2) cannabinoid receptors and the GPR55 receptor to regulate bone cell function through a variety of signaling pathways. Our research has shown that the CB1 receptor plays a key role in regulating osteoclast function and bone mass since deficiency of CB1 or pharmacological inhibitors of CB1 prevent bone loss by inhibiting bone resorption (Idris et al Nature Medicine 2005;11:774-779). Remarkably however the CB1 also regulates bone formation and protects against age-related osteoporosis by regulating differentiation of bone marrow stem cells into osteoblasts and adipocytes (Idris et al. Cell Metabolism 2009;10:139-147). The CB2 receptor also seems to protect against bone loss since CB2 deficiency can lead to osteoporosis but this is only apparent with increasing age (Ofek et al PNAS 2006;103:696-701) The GPR55 receptor has recently been shown to play a role in regulating bone resorption (Whyte et al PNAS 2009;106:16511-16516). So far most of the research on cannabinoids and bone has involved experimental models, but clinical studies are now being initiated to determine whether recreational use of cannabis has positive or negative effects on the skeleton.
	Updated: Wed, 22nd September, 2010