Cannabinoids and bone regeneration

Apostu, Dragoș; Lucaciu, Ondine; Meşter, Alexandru; Benea, Horea; Oltean‐Dan, Daniel; Onişor, Florin; Băciuţ, Mihaela; Bran, Simion

doi:10.1080/03602532.2019.1574303

Cited by 40 publications

(33 citation statements)

References 63 publications

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“…In this regard, CB1 receptors are proposed to transmit retrograde signals which inhibit the release of the sympathetic nervous system transmitter norepinephrine and thereby stimulate bone formation [300,301]. As a result, CB1/CB2 agonists and antagonists are under investigation for their therapeutic capacity in bone regeneration [302]. Additionally, the phytocannabinoid cannabidiol was identified to stimulate collagen crosslinks and stabilize callus formation by stimulating lysyl-hydroxylase activity in osteoblasts while respecting the BBB, which promotes cannabidiol as a treatment option for osteoporosis [302] and impaired fracture healing [303].…”

Section: Central Regulationmentioning

confidence: 99%

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Otto

Knapstein

Jahn

et al. 2020

IJMS

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As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.

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Section: Central Regulationmentioning

confidence: 99%

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Otto

Knapstein

Jahn

et al. 2020

IJMS

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“…Previous studies have proved that the existence of endocannabinoid system in bones, blood vessels, spleen, intestines, brain, and many peripheral tissues [ 45 ]. Compared with CB1, GPR55, GPR119, TPRV1, TPRV4, and other related receptors, the expression level of CB2 is higher in bone tissue [ 46 ]. Selective CB2 agonists have also been shown to play a role in diseases such as colon cancer [ 47 ], inflammatory bowel disease [ 48 ], and atherosclerosis [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Activation of cannabinoid receptor 2 alleviates glucocorticoid-induced osteonecrosis of femoral head with osteogenesis and maintenance of blood supply

et al. 2021

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In glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3β/β-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.

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“…Of note, GPR55 can form heterodimers with other receptors, and this interaction might affect their reciprocal surface expression, and in particular, their signal transduction [53]. Previous studies have demonstrated interactions between GPR55 and the cannabinoid receptor CB 2 , with both expressed and shown to have roles in bone metabolism [10,54]. Furthermore, the cross-talk between GPR55 and the two cannabinoid receptors is further complicated through the modulation of integrin clustering [55].…”

Section: Discussionmentioning

confidence: 99%

“…GPR55 is widely expressed in several mammalian tissues, including breast, adipose tissue, testes and spleen [6], and several regions of the brain [7]. GPR55 has been implicated in different pathophysiological conditions, such as vascular functions [8], bone turnover [9,10], neuropathic/ in ammatory pain [11,12], motor coordination [13], central nervous system disorders [14,15], metabolic dysfunction [5,16], immune dysregulation [17] and alterations that drive malignant cell growth [18,19].…”

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confidence: 99%

Peptide targeting of the lysolipid-sensing GPR55 for osteoclastogenesis tuning

Mosca¹,

Mangini²,

Barba³

et al. 2020

Preprint

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Background: The G-protein-coupled receptor GPR55 has been implicated in multiple biological activities, which has fuelled interest in its functional targeting. Its controversial pharmacology and the regulation often species dependent impacted the potential translation of preclinical data involving GPR55.Results: With the aim to identify novel GPR55 regulators, we have started investigating the lysophosphatidylinositol (LPI)-induced GPR55-mediated signal transduction. HeLa cells silenced for their endogenous receptor, by stable expression of a short-hairpin RNA specific for GPR55 5’-UTR, were the expression system for wild-type and mutated GPR55 that allowed the definition of the requirement of GPR55 Lys80 for LPI-induced MAPK activation and receptor internalisation. In RAW264.7 macrophages, GPR55 pathways were investigated by Gpr55 silencing using small-interfering RNAs, demonstrating that LPI increased intracellular Ca2+ levels and induced actin filopodium formation through GPR55 activation. Furthermore, LPI/GPR55 axis was shown to have an active role in the osteoclastogenesis of precursor RAW264.7 cells induced by the ‘receptor-activator of nuclear factor kappa-B ligand’ (RANKL). Indeed, this differentiation into mature osteoclasts was associated with 14-fold increase in Gpr55 mRNA levels. Moreover, GPR55 silencing or antagonism impaired the RANKL-induced transcription of the osteoclastogenesis markers: ‘nuclear factor of activated T-cells, cytoplasmic 1’, matrix metalloproteinase-9, cathepsin-K, tartrate-resistant acid phosphatase, and the calcitonin receptor, as evaluated by real-time PCR. Phage display was previously used to identify peptides that bind to GPR55. Here, the GPR55-specific peptide-P1 strongly inhibited osteoclast maturation of RAW264.7 macrophages.Conclusions: As bone-metastasis development can be blocked through inhibition of bone resorption, osteoclasts are strong targets for anti-metastatic treatments, and such GPR55-specific peptides might represent useful tools for novel therapeutic approaches.

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Cannabinoids and bone regeneration

Cited by 40 publications

References 63 publications

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Crosstalk of Brain and Bone—Clinical Observations and Their Molecular Bases

Activation of cannabinoid receptor 2 alleviates glucocorticoid-induced osteonecrosis of femoral head with osteogenesis and maintenance of blood supply

Peptide targeting of the lysolipid-sensing GPR55 for osteoclastogenesis tuning

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