Osteoblast Maturation Suppressed Osteoclastogenesis in Coculture with Bone Marrow Cells

Deyama, Yoshiaki; Takeyama, Sadaaki; Koshikawa, Mino; Shirai, Yoichi; Yoshimura, Yoshitaka; Nishikata, Makoto; Suzuki, Kuniaki; Matsumoto, Akira

doi:10.1006/bbrc.2000.3127

Cited by 39 publications

(28 citation statements)

References 25 publications

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“…RANKL expression decreases with osteoblast differentiation (Deyama et al, 2000;Atkins et al, 2003) and some researchers (De Boer et al, 2004), including ourselves (unpublished observations) have demonstrated that Wnt signalling impairs the osteogenic differentiation of human mesenchymal stem cells in vitro. However, we feel that this is unlikely to solely account for the Wnt-induced down regulation of pro-osteoclastogenic cytokines.…”

Section: Discussionmentioning

confidence: 95%

Wnt signalling in osteoblasts regulates expression of the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitro

Spencer

Utting

Etheridge

et al. 2006

Journal of Cell Science

304

220

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Reports implicating Wnt signalling in the regulation of bone mass have prompted widespread interest in the use of Wnt mimetics for the treatment of skeletal disorders. To date much of this work has focused on their anabolic effects acting on cells of the osteoblast lineage. In this study we provide evidence that Wnts also regulate osteoclast formation and bone resorption, through a mechanism involving transcriptional repression of the gene encoding the osteoclastogenic cytokine receptor activator of NFκB ligand (RANKL or TNFSF11) expressed by osteoblasts. In co-cultures of mouse mononuclear spleen cells and osteoblasts, inhibition of GSK3β with LiCl or exposure to Wnt3a inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated cells compared with controls. However, these treatments had no consistent effect on the differentiation, survival or activity of osteoclasts generated in the absence of supporting stromal cells. Activation of Wnt signalling downregulated RANKL mRNA and protein expression, and overexpression of fulllength β-catenin, but not transcriptionally inactive β-catenin ΔC(695-781), inhibited RANKL promoter activity. Since previous studies have demonstrated an absence of resorptive phenotype in mice lacking LRP5, we determined expression of a second Wnt co-receptor LRP6 in human osteoblasts, CD14+ osteoclast progenitors and mature osteoclasts. LRP5 expression was undetectable in CD14-enriched cells and mature human osteoclasts, although LRP6 was expressed at high levels by these cells. Our evidence of Wnt-dependent regulation of osteoclastogenesis adds to the growing complexity of Wnt signalling mechanisms that are now known to influence skeletal function and highlights the requirement to develop novel therapeutics that differentially target anabolic and catabolic Wnt effects in bone.

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Section: Discussionmentioning

confidence: 95%

Wnt signalling in osteoblasts regulates expression of the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitro

Spencer

Utting

Etheridge

et al. 2006

Journal of Cell Science

304

220

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“…It is also pertinent that lower osteoblast TNFRSF11B:TNFSF11 ratios (observed in OP osteoblasts) are likely to promote bone resorption assuming correlative post-translational trends, suggesting that such remodelling activities will predominate in trabecular type bone and will also be more marked in bone from OP than OA (and normal) patient groups. RANKL and OPG protein levels were not measured herein, however previous studies have demonstrated close correlation of osteogenic protein expression to mRNA levels (Born et al, 2009;Deyama et al, 2000;Hofbauer et al, 1999;Rickard et al, 1996;Shea et al, 2000).…”

Section: Shah Et Al Bone Type-related Differences In Human Osteoblmentioning

confidence: 87%

Local origins impart conserved bone type-related differences in human osteoblast behaviour

Shah

Gburcik²,

Reilly³

et al. 2015

eCM

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Osteogenic behaviour of osteoblasts from trabecular, cortical and subchondral bone were examined to determine any bone type-selective differences in samples from both osteoarthritic (OA) and osteoporotic (OP) patients. Cell growth, differentiation; alkaline phosphatase (TNAP) mRNA and activity, Runt-related transcription factor-2 (RUNX2), SP7-transcription factor (SP7), bone sialoprotein-II (BSP-II), osteocalcin/bone gammacarboxyglutamate (BGLAP), osteoprotegerin (OPG, TNFRSF11B), receptor activator of nuclear factor-κβ ligand (RANKL, TNFSF11) mRNA levels and proangiogenic vascular endothelial growth factor-A (VEGF-A) mRNA and protein release were assessed in osteoblasts from paired humeral head samples from age-matched, human OA/OP (n = 5/4) patients. Initial outgrowth and increase in cell number were significantly faster (p < 0.01) in subchondral and cortical than trabecular osteoblasts, in OA and OP, and this bone type-related differences were conserved despite consistently faster growth in OA. RUNX2/SP7 levels and TNAP mRNA and protein activity were, however, greater in trabecular than subchondral and cortical osteoblasts in OA and OP. BSP-II levels were significantly greater in trabecular and lowest in cortical osteoblasts in both OA and OP. In contrast, BGLAP levels showed divergent bone type-selective behaviour; highest in osteoblasts from subchondral origins in OA and trabecular origins in OP. We found virtually identical bone type-related differences, however, in TNFRSF11B:TNFSF11 in OA and OP, consistent with greater potential for paracrine effects on osteoclasts in trabecular osteoblasts. Subchondral osteoblasts (OA) exhibited highest VEGF-A mRNA levels and release. Our data indicate that human osteoblasts in trabecular, subchondral and cortical bone have inherent, programmed diversity, with specific bone type-related differences in growth, differentiation and pro-angiogenic potential in vitro.

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“…Osteoblastic factors can stimulate osteoblast proliferation, increasing the population of early osteoblasts (Coffman 2003). The enlarged pool of early osteoblasts responds to osteolytic factors by increased expression of RANKL (Deyama et al 2000, Geoffroy et al 2002. Recently Yi et al (2002) overexpressed PDGF B-chain in MDA-MB-231 cells and observed osteosclerotic rather than osteolytic metastases.…”

Section: Osteoblastic Metastasismentioning

confidence: 99%

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

Clines

Guise²

2005

Endocr Relat Cancer

230

211

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Calcium homeostasis is a tightly regulated process involving the co-ordinated efforts of the skeleton, kidney, parathyroid glands and intestine. Neoplasms can alter this homeostasis indirectly through the production of endocrine factors resulting in humoral hypercalcaemia of malignancy. Relatively common with breast and lung cancer, this paraneoplastic condition is most often due to tumour production of parathyroid hormone-related protein and ensuing increased osteoclastic bone resorption. Although control of hypercalcaemia is generally successful, the development of this complication is associated with a poor prognosis. The metastasis of tumour cells to bone represents another skeletal complication of malignancy. As explained in the 'seed and soil' hypothesis, bone represents a fertile ground for cancer cells to flourish. The molecular mechanisms of this mutually beneficial relationship between bone and cancer cells are beginning to be understood. In the case of osteolytic bone disease, tumour-produced parathyroid hormone-related protein stimulates osteoclasts that in turn secrete tumour-activating transforming growth factor-b that further stimulates local cancer cells. This 'vicious cycle' of bone metastases represents reciprocal bone/ cancer cellular signals that likely modulate osteoblastic bone metastatic lesions as well. The development of targeted therapies to either block initial cancer cell chemotaxis, invasion and adhesion or to break the 'vicious cycle' is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.

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Osteoblast Maturation Suppressed Osteoclastogenesis in Coculture with Bone Marrow Cells

Cited by 39 publications

References 25 publications

Wnt signalling in osteoblasts regulates expression of the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitro

Wnt signalling in osteoblasts regulates expression of the receptor activator of NFκB ligand and inhibits osteoclastogenesis in vitro

Local origins impart conserved bone type-related differences in human osteoblast behaviour

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

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