Cardiotrophin-1 Is an Osteoclast-Derived Stimulus of Bone Formation Required for Normal Bone Remodeling

Walker, Emma C; McGregor, Narelle E; Poulton, Ingrid J; Pompolo, Sueli; Allan, Elizabeth; Quinn, J; Gillespie, Matthew T.; Martın, Thomas; Sims, Natalie A.

doi:10.1359/jbmr.080706

Cited by 175 publications

(179 citation statements)

References 47 publications

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“…Although osteoclast numbers were increased significantly, osteoclast function was impaired, as indicated by increased cartilage remnants within the trabecular bone (29)(30)(31). This impairment in osteoclast function is consistent with our observed effects of O-1602 on osteoclasts in vitro and a role for GPR55 in stimulating osteoclast activity.…”

Section: Discussionsupporting

confidence: 89%

The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

Whyte

Ryberg

Sims

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

294

328

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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 CB 1 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.A role for the endocannabinoid system (1) in the regulation of bone mass has been demonstrated recently, because mice lacking either of the cannabinoid receptors CB 1 or CB 2 have abnormal bone phenotypes. Furthermore, cannabinoid receptor agonists and inverse agonists reduce bone loss in mice following ovariectomy and have direct effects on both bone-resorbing cells (osteoclasts) and bone-forming cells (osteoblasts) in vitro (2, 3).In some systems such as the vasculature, there is considerable evidence for a role of non-CB 1 /non-CB 2 receptors in mediating some of the effects of certain cannabinoid ligands (for review, see ref. 4). Such non-CB 1 /non-CB 2 effects have been observed with a range of cannabinoid ligands including certain endocannabinoids and the phytocannabinoid-like compound O-1602; these effects are antagonized by the cannabis constituent cannabidiol (CBD) (4). Recently, the G protein-coupled receptor GPR55 has been shown to be activated by O-1602 (EC 50 ϭ 13 nM) and antagonized by CBD (IC 50 ϭ 445 nM) (5-8). In contrast, these compounds have low affinity (5-30 M) for CB 1 and CB 2 receptors (9, 10). GPR55 also is activated by the bioactive lipid, L-␣-lysophosphatidylinositol (LPI) (11,12).The physiological role(s) of GPR55 remains unknown. Given the apparent role of CB 1 and CB 2 in regulating bone mass, we examined whether GPR55 is expressed by osteoblasts and osteoc...

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Section: Discussionsupporting

confidence: 89%

The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

Whyte

Ryberg

Sims

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

294

328

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“…For microarray validation experiments, Kusa 4b10 were serum starved (2% FBS) on day 16 of differentiation for 18 h prior to treatment with the indicated doses of PTH(1-34) (10 nM), and mouse CT-1 or mouse OSM (50 ng/ml; R&D Systems) for the times indicated. Mouse primary osteoblasts were prepared by enzymatic digestion of calvariae of newborn wild-type (WT) C57BL/6 mice (1-2 days old) (20,21). Mineralized nodules were stained by von Kossa with 3% silver nitrate and fixation with 0.1% sodium thiosulfate.…”

Section: Methodsmentioning

confidence: 99%

“…The gp130-signaling cytokines OSM and CT-1 have been reported to have similar effects on bone formation to PTH in that they stimulate osteoblast differentiation and inhibit adipogenesis (20,21). Mice null for OSM receptor or CT-1 demonstrated impaired bone formation and high marrow adiposity (20,21).…”

mentioning

confidence: 99%

Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment

Quach

Walker

Allan

et al. 2011

Journal of Biological Chemistry

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Osteoblasts and adipocytes are derived from common mesenchymal progenitor cells. The bone loss of osteoporosis is associated with altered progenitor differentiation from an osteoblastic to an adipocytic lineage. cDNA microarrays and quantitative real-time PCR (Q-PCR) were carried out in a differentiating mouse stromal osteoblastic cell line, Kusa 4b10, to identify gene targets of factors that stimulate osteoblast differentiation including parathyroid hormone (PTH) and gp130-binding cytokines, oncostatin M (OSM) and cardiotrophin-1 (CT-1). Zinc finger protein 467 (Zfp467) was rapidly downregulated by PTH, OSM, and CT-1. Retroviral overexpression and RNA interference for Zfp467 in mouse stromal cells showed that this factor stimulated adipocyte formation and inhibited osteoblast commitment compared with controls. Regulation of adipocyte markers, including peroxisome proliferator-activated receptor (PPAR) ␥, C/EBP␣, adiponectin, and resistin, and late osteoblast/osteocyte markers (osteocalcin and sclerostin) by Zfp467 was confirmed by Q-PCR. Intra-tibial injection of calvarial cells transduced with retroviral Zfp467 doubled the number of marrow adipocytes in C57Bl/6 mice compared with vector control-transduced cells, providing in vivo confirmation of a pro-adipogenic role of Zfp467. Furthermore, Zfp467 transactivated a PPAR-response element reporter construct and recruited a histone deacetylase complex. Thus Zfp467 is a novel co-factor that promotes adipocyte differentiation and suppresses osteoblast differentiation. This has relevance to therapeutic interventions in osteoporosis, including PTH-based therapies currently available, and may be of relevance for the use of adipose-derived stem cells for tissue engineering.Osteoblasts and adipocytes are derived from a common subpopulation of mesenchymal stem cell (MSC) 4 progenitors.MSC lineage commitment is dependent on the expression of key transcription factors that, on induction, initiate a cascade of events culminating in cellular differentiation and development. Among the transcription factors regulated, osteoblast differentiation requires expression of Runx2 (1, 2) to commit progenitors to preosteoblasts, with Osterix (3), ATF4 (4), and AP-1 (5) promoting their transition to functional osteoblasts. Alternately, adipocytic differentiation requires expression of different key regulators, peroxisome proliferator-activated receptor ␥ (PPAR␥) (6) and members of the CCAAT/enhancer-binding protein family (C/EBPs) (7). Because osteoblasts and adipocytes are derived from common progenitors, lineage determination of precursor cells to osteoblasts results in a proportional decrease in adipogenesis. This inverse relationship is observed clinically; an increase in marrow adiposity is associated with age-related osteoporosis (8) and conditions that induce bone loss, such as ovariectomy (9) and immobilization (10). Conversely, high bone mass due to increased osteoblast commitment is associated with reduced adipocyte differentiation (5). The molecular mechanisms by which lineage...

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“…Bone-increasing effect of CT-1 as a coupling factor is not obvious in adult bone remodeling. 24 Wnt10b was also identified in the culture medium of human osteoclasts as a stimulator of mineralization activity of osteoblastic cells. 25 Wnt10b is known to be involved in the canonical Wnt / -catenin pathway that is essential for osteoblast differentiation and bone formation.…”

Section: Bone Cell Communication Factors T Negishi-koga and H Takayanagimentioning

confidence: 96%

“…24 These mice have a large number of dysfunctional osteoclasts, which do not appear to stimulate bone formation. These observations suggest that CT-1, at least in neonates, has a predominant role in promoting osteoblast differentiation over other stimulating factors derived from osteoclasts.…”

Section: Bone Cell Communication Factors T Negishi-koga and H Takayanagimentioning

confidence: 99%

Bone cell communication factors and Semaphorins

Negishi-Koga

Takayanagi

2012

BoneKEy Reports

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-6396/12 www.nature.com/bonekey IntroductionThe bony skeleton enables various crucial processes, such as locomotive activity, the storage of calcium and the harboring of hematopoietic stem cells. Bone is a dynamic organ that is continuously being broken down by osteoclasts and subsequently rebuilt with new bone by osteoblasts throughout the course of one ' s adult life. These activities occur in response to various hormones, cytokines, chemokines and biomechanical external stimuli. 1,2 This process, called bone remodeling, is a prerequisite for the normal bone homeostasis that maintains both bone quality and strength. 2 An imbalance of bone resorption and formation is often central to metabolic bone diseases in humans and animals. For example, excessive resorption by osteoclasts results in pathological bone destruction, as seen in osteoporosis, autoimmune arthritis, Paget ' s disease, periodontitis and bone tumors. 1,3,4 Therefore, bone remodeling must be regulated both temporally and spatially so that the aged or damaged bone is replaced by an essentially equivalent amount of new bone. 1,5,6 The bone remodeling is carried out within the temporary anatomic structures, so-called basic multicellular unit (BMU), which consists of a group of osteoclasts in front forming the cutting cone and a group of osteoblasts behind forming the closing cone, by associating with blood supply and the peripheral innervation. 7,8 The bone remodeling is a cycle consisting of three phases: ' initiation ' of bone resorption by osteoclasts, the ' transition ' from resorption to new bone formation (also well known as a ' reversal ' period) and the ' bone formation ' ( Figure 1 ). 6,9 The entire process is achieved by the coordinated actions of osteoclasts, osteoblasts and other osteoblast lineage cells, including bone-lining cells and osteocytes. The most obvious example is the osteoclastogenesis regulatory system by receptor activator of nuclear-B ligand (RANKL) and its decoy receptor osteoprotegerin (OPG), which are produced by osteoblast lineage cells. However, key questions remain REVIEW Bone cell communication factors and SemaphorinsTakako Negishi-Koga 1 , 2 , 3 and Hiroshi Takayanagi 1 , 2 , 3 , 4 Bone tissue is continuously renewed throughout adult life by a process called ' remodeling ' , which involves a dynamic interplay among bone cells including osteoclasts, osteoblasts and osteocytes. For example, a tight coupling between bone resorption and formation is essential for the homeostasis of the skeletal system. Studies on the coupling mechanism in physiological and pathological settings have revealed that osteoclasts or osteoclastic bone resorption promote bone formation through the production of diverse coupling factors. The classical coupling factors are the molecules that promote bone formation after resorption, but there may be distinct mechanisms at work in various phases of bone remodeling. A recent study revealed that the Semaphorin 4D expressed by osteoclasts inhibits bone formation, which represents a mechanism by which...

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Cardiotrophin-1 Is an Osteoclast-Derived Stimulus of Bone Formation Required for Normal Bone Remodeling

Cited by 175 publications

References 47 publications

The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment

Bone cell communication factors and Semaphorins

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