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The Putative Cannabinoid Receptor Gpr55 Affects Osteoclast Function In Vitro And Bone Mass In Vivo

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GPR55 is a G protein-coupled receptor recently shown to be activated by certain cannabinoids and by lysophosphatidylinositol (LPI). However, the physiological role of GPR55 remains unknown. Given the recent finding that the cannabinoid receptors CB1 and CB2 affect bone metabolism, we examined the role of GPR55 in bone biology. GPR55 was expressed in human and mouse osteoclasts and osteoblasts; expression was higher in human osteoclasts than in macrophage progenitors. Although the GPR55 agonists O-1602 and LPI inhibited mouse osteoclast formation in vitro, these ligands stimulated mouse and human osteoclast polarization and resorption in vitro and caused activation of Rho and ERK1/2. These stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55−/− macrophages and by the GPR55 antagonist cannabidiol (CBD). Furthermore, treatment of mice with this non-psychoactive constituent of cannabis significantly reduced bone resorption in vivo. Consistent with the ability of GPR55 to suppress osteoclast formation but stimulate osteoclast function, histomorphometric and microcomputed tomographic analysis of the long bones from male GPR55−/− mice revealed increased numbers of morphologically inactive osteoclasts but a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage. These data reveal a role of GPR55 in bone physiology by regulating osteoclast number and function. In addition, this study also brings to light an effect of both the endogenous ligand, LPI, on osteoclasts and of the cannabis constituent, CBD, on osteoclasts and bone turnover in vivo.




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An osteoclast (from the Greek words for "bone" (Οστό) and "broken" (κλαστός)) is a type of bone cell that resorbs boney tissue. This function is critical in the maintenance and repair of compact bones in the mammalian skeleton. These bones are stronger than aluminum on a weight basis by being a composite material of approximately equal amounts of hydrated protein and mineral.[1] The osteoclast disassembles this very strong composite at a molecular level by secreting acid and a collagenase. This process is known as bone resorption. Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue: osteoblasts form bone, osteoclasts re-absorb bone.


Bone resorption is the process by which osteoclasts break down bone[1] and release the minerals, resulting in a transfer of calcium from bone fluid to the blood.[2]

The osteoclasts are multi-nucleated cells that contain numerous mitochondria and lysosomes. These are the cells responsible for the resorption of bone. Osteoclasts are generally present on the outer layer of bone, just beneath the periosteum. Attachment of the osteoclast to the osteon begins the process. The osteoclast then induces an infolding of its cell membrane and secretes collagenase and other enzymes important in the resorption process. High levels of calcium, magnesium, phosphate and products of collagen will be released into the extracellular fluid as the osteoclasts tunnel into the mineralized bone. Osteoclasts are also prominent in the tissue destruction commonly found in psoriatic arthritis and other rheumatology related disorders.

The human body is in a constant state of bone remodeling.[3] Bone is resorbed by osteoclasts, and is deposited by osteoblasts in a process called ossification. Osteocyte activity also plays a key role in this process. Conditions that result in a decrease in bone mass, can either be caused by an increase in resorption, or a decrease in ossification.

During childhood, bone formation exceeds resorption, but as the aging process occurs, resorption exceeds formation.


They're showing that GPR55 is a target to consider.


The physiological role(s) of GPR55 remains unknown. Given the apparent role of CB1 and CB2 in regulating bone mass, we examined whether GPR55 is expressed by osteoblasts and osteoclasts and whether this receptor regulates bone cell function in vitro and in vivo. We present evidence that GPR55 plays a role in bone physiology, with major implications for the development of GPR55- and CBD-related therapeutics.


I really wish we had more help deciphering all of this. There are some parts that I'm not familiar with. But, I can try to read between the lines.




GPR55 Knockout Mice Have Increased Bone Mass.

In 12-week-old male GPR55−/− mice, bone volume [bone volume (BV)/tissue volume (TV)] was significantly increased in the tibia and femur compared with wild-type littermates, together with a significant increase in trabecular number, trabecular connectivity (trabecular pattern factor), and a transition from rod-like to plate-like trabecular structure (structure modulus index) in the femur (Fig. 4 A and B). These changes were not seen in female GPR55−/− mice of the same age. No significant changes in cortical bone volume were detected in male or female mice compared with GPR55−/− mice of the same age.



CBD is a GPR55 blocker (so is either magnolol or honokiol, not sure which). Mice that don't have GPR55 receptors show an increase in bone mass. GPR55 blockers may help to increase bone mass by inhibiting bone resorption?




The GPR55 Antagonist CBD Inhibits Bone Resorption in Vivo.

CBD has been estimated to have a half-life of 2–5 days in humans (15, 16). Treatment of male mice for 8 weeks with 10 mg/kg CBD (3 times per week) significantly decreased the level of serum type 1 collagen C-terminal telopeptide fragments (CTX), a biochemical marker of bone resorption, by 18% (P < 0.05) (vehicle control = 22.47 ng/L; CBD-treated = 18.27 ng/L). Microtomographic (μCT) analysis of the proximal tibiae also revealed a trend toward increased BV/TV (+ 10%) and trabecular number (+ 10%), with a decrease in trabecular separation (− 7%), trabecular pattern factor (− 5%), and structure modulus index (− 8%) in the tibia of the CBD-treated mice relative to control. These findings were consistent with a decrease in bone resorption in CBD-treated mice, although these changes were not statistically significant over this treatment schedule.


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