*Endocannabinoid Control of Skeleton

BONES – cannabinoid

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Bone. 2009 Mar;44(3):476-84. Epub 2008 Nov 14.

Links

The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption.

Rossi F, Siniscalco D, Luongo L, De Petrocellis L, Bellini G, Petrosino S, Torella M, Santoro C, Nobili B, Perrotta S, Di Marzo V, Maione S.

Department of Pediatrics, Second University of Naples, Naples, Italy.

The presence of the endocannabinoid/endovanilloid proteins in human osteoclasts will likely have implications for the management of bone demineralization associated syndrome (i. e. osteoporosis).

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Endocrinology. 2008 Nov;149(11):5619-26. Epub 2008 Jul 17.

Links

Regulation of bone mass, osteoclast function, and ovariectomy-induced bone loss by the type 2 cannabinoid receptor.

Idris AI, Sophocleous A, Landao-Bassonga E, van’t Hof RJ, Ralston SH.

Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.

The endocannabinoid system has recently been shown to play a role in the regulation of bone metabolism. The type 2 cannabinoid receptor (CB2) has been reported to regulate bone mass, but conflicting results have been reported with regard to its effects on bone resorption and osteoclast function. Here we investigated the role that CB2 plays in regulating bone mass and osteoclast function using a combination of pharmacological

We conclude that CB2 regulates osteoclast formation and bone resorption in vitro and that under conditions of increased bone turnover, such as after ovariectomy, CB2 regulates bone loss. These observations indicate that CB2 regulates osteoclast formation and contributes to ovariectomy-induced bone loss and demonstrate that cannabinoid receptor antagonists/inverse agonists may be of value in the treatment of bone diseases characterized by increased osteoclast activity.

PMID: 18635663 [PubMed – indexed for MEDLINE

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FASEB J. 2008 Jan;22(1):285-94. Epub 2007 Aug 17.

Links

The cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling.

Tam J, Trembovler V, Di Marzo V, Petrosino S, Leo G, Alexandrovich A, Regev E, Casap N, Shteyer A, Ledent C, Karsak M, Zimmer A, Mechoulam R, Yirmiya R, Shohami E, Bab I.

Bone Laboratory, Hadassah School of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Ann N Y Acad Sci. 2007 Nov;1116:414-22. Epub 2007 Jul 23.

Links

Regulation of skeletal remodeling by the endocannabinoid system.

Bab IA.

Bone Laboratory, The Hebrew University of Jerusalem, Jerusalem, Israel. babi@cc.huji.ac.il

Mol Pharmacol. 2006 Sep;70(3):786-92. Epub 2006 Jun 13.

Links

Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling.

Tam J, Ofek O, Fride E, Ledent C, Gabet Y, Müller R, Zimmer A, Mackie K, Mechoulam R, Shohami E, Bab I.

Bone Laboratory, Hebrew University of Jerusalem, PO Box 12272, Jerusalem 91120, Israel.

Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):696-701. Epub 2006 Jan 9.

Links

Peripheral cannabinoid receptor, CB2, regulates bone mass.

Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I.

Bone Laboratory, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

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Hu et al 2006

Cancer Genet Cytogenet. 2006 Aug;169(1):12-20.

Links

Brain-derived neurotrophic factor promotes growth and migration of multiple myeloma cells.

Hu Y, Sun CY, Wang HF, Guo T, Wei WN, Wang YD, He WJ, Wu T, Tan H, Wu TC.

Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Dadao, Wuhan 430022, PR China.

The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow microenvironment, which support proliferation and survival of malignant plasma cells. Previous study defined a brain-derived neurotrophic factor-tyrosine kinase receptor B (BDNF /TrkB ) axis in myeloma and autocrine growth stimulation by BDNF  in various tumor cells.

We examined the biological effects of BDNF  on MM cells. … we observed that both BDNF and its high-affinity receptor TrkB  are expressed by MM cell lines (RPMI 8226, U266, and KM3) and primary MM cells. Functional studies revealed that BDNF  was a potent growth factor for MM.

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Linda note:  We will find the most common language with which to talk about all aspects of our species in our genes and in their interactions with our life in our bodies.  There is no other way – until we are ready to move onto other levels like the Chinese biophysicist talk about – our electromagnetic body.

++++

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Bone. 2009 Mar;44(3):476-84. Epub 2008 Nov 14.

Links

The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption.

Rossi F, Siniscalco D, Luongo L, De Petrocellis L, Bellini G, Petrosino S, Torella M, Santoro C, Nobili B, Perrotta S, Di Marzo V, Maione S.

Department of Pediatrics, Second University of Naples, Naples, Italy.

Recent studies suggest a role for the endocannabinoid/endovanilloid anandamide in the regulation of bone resorption/formation balance in mice.

The presence of the endocannabinoid/endovanilloid proteins in human osteoclasts will likely have implications for the management of bone demineralization associated syndrome (i. e. osteoporosis).

PMID: 19059369 [PubMed – indexed for MEDLINE

+++++++++++++++

Endocrinology. 2008 Nov;149(11):5619-26. Epub 2008 Jul 17.

Links

Regulation of bone mass, osteoclast function, and ovariectomy-induced bone loss by the type 2 cannabinoid receptor.

Idris AI, Sophocleous A, Landao-Bassonga E, van’t Hof RJ, Ralston SH.

Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.

The endocannabinoid system has recently been shown to play a role in the regulation of bone metabolism. The type 2 cannabinoid receptor (CB2) has been reported to regulate bone mass, but conflicting results have been reported with regard to its effects on bone resorption and osteoclast function. Here we investigated the role that CB2 plays in regulating bone mass and osteoclast function using a combination of pharmacological and genetic approaches.

We conclude that CB2 regulates osteoclast formation and bone resorption in vitro and that under conditions of increased bone turnover, such as after ovariectomy, CB2 regulates bone loss. These observations indicate that CB2 regulates osteoclast formation and contributes to ovariectomy-induced bone loss and demonstrate that cannabinoid receptor antagonists/inverse agonists may be of value in the treatment of bone diseases characterized by increased osteoclast activity.

PMID: 18635663 [PubMed – indexed for MEDLINE

+++++++++++

Bab 2007

Ann N Y Acad Sci. 2007 Nov;1116:414-22. Epub 2007 Jul 23.

Links

Regulation of skeletal remodeling by the endocannabinoid system.

Bab IA.

Bone Laboratory, The Hebrew University of Jerusalem, Jerusalem, Israel. babi@cc.huji.ac.il

Since the discovery of the endocannabinoid system, its presence and involvement have been reported in a handful of biological systems.  Isn’t that an understatement?

Recently, the

skeleton

has been identified as a major endocannabinoid target

….through both the neuronal CB1 and

….predominantly peripheral CB2 cannabinoid receptors.

CB1 is present in sympathetic nerve terminals in bone,

…..whereas CB2 is expressed in osteoblasts and osteoclasts,

….the respective bone-forming and -resorbing cells.

Furthermore, the

skeleton

appears as the main system

physiologically regulated by

CB2.

CB2-deficient mice show a markedly accelerated age-related bone loss and the

CB2 locus in women is associated with low bone density and osteoporotic fractures.

Since activation of CB2 attenuates experimentally induced bone loss by inhibiting bone resorption and stimulating bone formation, and because synthetic cannabinoids are stable and orally available, a therapy based on synthetic CB2 agonists is a promising novel target for antiosteoporotic drug development.

Again, what other cannabinoid operations would taking these drugs impact?

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Arch Biochem Biophys. 2008 May 15;473(2):231-6. Epub 2008 Mar 23.

Links

Regulation of bone remodeling by the central and peripheral nervous system.

Elefteriou F.

Vanderbilt University, Medicine, 2215 Garland Avenue, Medical Research Building IV Room, Nashville, TN 37232-0575, USA. florent.elefteriou@Vanderbilt.Edu

The homeostatic nature of bone remodeling has become a notion further supported lately by the demonstration that neuropeptides and their receptors regulate osteoblast and osteoclast function in vivo.

Following initial studies reporting the presence of nerves and nerve-derived products within the bone microenvironment and the expression of receptors for these neuropeptides in bone cells, new experimental and mechanistic evidence based on in vivo murine genetic and pharmacologic models recently demonstrated that inputs from the central and peripheral nervous system feed into the already complex regulatory machinery controlling bone remodeling.

The function of a number of “osteo-neuromediators” has been characterized, including norepinephrine and the beta2-adrenergic receptor, Neuropeptide Y and the Y1 and Y2 receptors, endocannabinoids and the CB1 and CB2 receptors, as well as dopamine, serotonin and their receptors and transporters, Calcitonin gene-related peptide, and neuronal NOS. This new body of evidence suggests that neurons in the central nervous system integrate clues from the internal and external milieux, such as energy homeostasis, glycemia or reproductive signals, with the regulation of bone remodeling.

The next major tasks in this new area of bone biology will be to understand, at the molecular level, the mechanisms by which common central neural systems regulate and integrate these major physiological functions, the relative importance of the central and peripheral actions of neuropeptides present in both compartments and their relationship, and how bone cells signal back to central centers, because the definition of a homeostatic function implies the existence of feedback signals.

Together, these findings shed a new light on the complexity of the mechanisms regulating bone remodeling and uncovered new potential therapeutic strategies for the design of bone anabolic treatments. This review summarizes the latest advances in this area, focusing on investigations based on in vivo animal studies.

PMID: 18410742 [PubMed – indexed for MEDLINE

++++++++++

Bab 2008

J Neuroendocrinol. 2008 May;20 Suppl 1:69-74.

Links

Endocannabinoids and the regulation of bone metabolism.

Bab I, Ofek O, Tam J, Rehnelt J, Zimmer A.

Bone Laboratory, The Hebrew University of Jerusalem, Jerusalem, Israel. babi@cc.huji.ac.il

anti-osteoporotic therapies

In mammals, including humans, bone metabolism is manifested as an ongoing modelling/remodelling process whereby the bone mineralised matrix is being continuously renewed.

Recently, the main components of the endocannabinoid system

have been reported in the skeleton.

Osteoblasts, the bone forming cells, and other cells of the osteoblastic lineage, as well as osteoclasts, the bone resorbing cells, and their precursors, synthesise the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG). CB(1) cannabinoid receptors are present in sympathetic nerve terminals in close proximity to osteoblasts.

Activation of these CB(1) receptors by elevated bone 2-AG levels communicates brain-to-bone signals as exemplified by traumatic brain injury-induced stimulation of bone formation. In this process, the retrograde CB(1) signalling inhibits noradrenaline release and alleviates the tonic sympathetic restrain of bone formation. CB(2) receptors are expressed by osteoblasts and osteoclasts. Their activation stimulates bone formation and suppresses bone resorption.

CB(2)-deficient mice display a markedly accelerated age-related bone loss.

Ovariectomy-induced bone loss can be both prevented and rescued by a CB(2) specific agonist.

Hence, synthetic CB(2) ligands, which are stable and orally available, provide a basis for developing novel anti-osteoporotic therapies, free of psychotropic effects.

The CNR2 gene (encoding CB(2)) in women is associated with low bone mineral density, offering an assay for identifying females at risk of developing osteoporosis.

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Involvement of neuronal cannabinoid receptor CB1 in regulation of bone mass and bone remodeling.

Tam J, Ofek O, Fride E, Ledent C, Gabet Y, Müller R, Zimmer A, Mackie K, Mechoulam R, Shohami E, Bab I.

Mol Pharmacol. 2006 Sep;70(3):786-92. Epub 2006 Jun 13.

PMID: 16772520 [PubMed – indexed for MEDLINE]

Peripheral cannabinoid receptor, CB2, regulates bone mass.

Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I.

Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):696-701. Epub 2006 Jan 9.

PMID: 16407142 [PubMed – indexed for MEDLINE]

Related Articles Free article in PMC | at journal site

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Bab & Zimmer 2008

Br J Pharmacol. 2008 Jan;153(2):182-8. Epub 2007 Dec 10.

Links

Cannabinoid receptors and the regulation of bone mass.

Bab I, Zimmer A.

Bone Laboratory, The Hebrew University of Jerusalem, Jerusalem, Israel. babi@cc.huji.ac.il

A functional endocannabinoid system is present in several mammalian organs and tissues.

……Recently, endocannabinoids and their receptors have been reported in the skeleton.

…..Osteoblasts, the bone forming cells, and

….osteoclasts, the bone resorbing cells,

….produce the endocannabinoids anandamide and 2-arachidonoylglycerol and express CB2 cannabinoid receptors.

Although CB2 has been implicated in pathological processes in the central nervous system and peripheral tissues,

the skeleton appears as the main system physiologically regulated by CB2.

CB2-deficient mice show a markedly accelerated age-related bone loss and the CNR2 gene (encoding CB2) in women is associated with low bone mineral density. The activation of CB2 attenuates ovariectomy-induced bone loss in mice by restraining bone resorption and enhancing bone formation. Hence synthetic CB2 ligands, which are stable and orally available, provide a basis for developing novel anti-osteoporotic therapies.

Activation of CB1

in sympathetic nerve terminals

in bone

inhibits norepinephrine release,

thus balancing the tonic sympathetic restrain of bone formation.

Low levels of CB1 were also reported in osteoclasts. CB1-null mice display a skeletal phenotype that is dependent on the mouse strain, gender and specific mutation of the CB1 encoding gene, CNR1.

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Patel & Elefteriou 2007

Calcif Tissue Int. 2007 May;80(5):337-47. Epub 2007 Apr 18.

Links

The new field of neuroskeletal biology.

Patel MS, Elefteriou F.

Department of Medical Genetics, University of British Columbia, C234, 4500 Oak Street, Vancouver, BC, V6H 3N1, Canada.

.

The fields of neuroscience and bone biology

have recently converged following the discovery

that bone remodeling

is directly regulated by the brain.

This work has defined bone remodeling as one of the cardinal physiological functions of the body, subject to homeostatic regulation and integrated with the other major physiological functions by the hypothalamus.

Central to this discovery was the definition of the adipocyte-derived hormone leptin as a regulator of both arms of bone remodeling, formation and resorption, through its action on the ventromedial hypothalamus and subsequently via the sympathetic nervous system to osteoblasts.

The characterization of the sympathetic nervous system as a regulator of bone remodeling has led to several large clinical studies demonstrating a

substantial protective effect of beta-blockers, particularly beta1-blockers, on fracture risk.

Studies in model organisms have reinforced the role of the central nervous system in the regulation of bone remodeling in vivo by the identification of

several additional genes, namely

cocaine and amphetamine regulated transcript (Cart), melanocortin 4 receptor (Mc4R),

neuropeptide Y (NPY),

Y2 receptor,

cannabinoid receptor CB1 (Cnbr1),

and the genes of the

circadian clock.

These genes have several common features, including high levels of expression in the hypothalamus

and the ability to regulate other major physiological functions

in addition to bone remodeling including

energy homeostasis,

body weight, and

reproduction.

We review the major pathways that define the new

field of neuroskeletal biology

and identify further avenues of inquiry.

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Elefteriou 2008

Arch Mal Coeur Vaiss. 2006 Mar;99(3):242-6.

Links

The endogenous cardiac cannabinoid system: a new protective mechanism against myocardial ischemia.

Lamontagne D, Lépicier P, Lagneux C, Bouchard JF.

Faculté de pharmacie, Université de Montréal, QC, Canada. daniel.lamontagne@umontreal.ca

The homeostatic nature of bone remodeling has become a notion further supported lately by the demonstration that neuropeptides and their receptors regulate osteoblast and osteoclast function in vivo. Following initial studies reporting the presence of nerves and nerve-derived products within the bone microenvironment and the expression of receptors for these neuropeptides in bone cells, new experimental and mechanistic evidence based on in vivo murine genetic and pharmacologic models recently demonstrated that inputs from the central and peripheral nervous system feed into the already complex regulatory machinery controlling bone remodeling.

The function of a number of “osteo-neuromediators” has been characterized, including

norepinephrine and the beta2-adrenergic receptor,

Neuropeptide Y and the Y1 and Y2 receptors,

endocannabinoids and the CB1 and CB2 receptors, as well as

dopamine,

serotonin and their receptors and transporters,

Calcitonin gene-related peptide, and

neuronal NOS.

This new body of evidence suggests that neurons in the central nervous system integrate clues from the internal and external milieux, such as energy homeostasis, glycemia or reproductive signals, with the regulation of bone remodeling.

The next major tasks in this new area of bone biology will be to understand, at the molecular level, the mechanisms by which common central neural systems regulate and integrate these major physiological functions, the relative importance of the central and peripheral actions of neuropeptides present in both compartments and their relationship, and

how bone cells signal back to central centers,

because the definition of a homeostatic function

implies the existence of

feedback signals.

Cool!!  So bones can TALK!!!!

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