The Role of Calcium and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) in Human Osteoclast Formation and Resorption

Abstract Purpose of Review The purpose of this review is to explore the role of monocyte chemoattractant protein-1 (MCP-1 or CCL2) in the processes that underpin bone remodelling, particularly the action of osteoblasts and osteoclasts, and its role in the development and metastasis of cancers that target the bone. Recent Findings MCP-1 is a key mediator of osteoclastogenesis, being the highest induced gene during intermittent treatment with parathyroid hormone (iPTH), but also regulates catabolic effects of continuous PTH on bone including monocyte and macrophage recruitment, osteoclast formation and bone resorption. In concert with PTH-related protein (PTHrP), MCP-1 mediates the interaction between tumour-derived factors and host-derived chemokines to promote skeletal metastasis. In breast and prostate cancers, an osteolytic cascade is driven by tumour cell–derived PTHrP that upregulates MCP-1 in osteoblastic cells. This relationship between PTHrP and osteoblastic expression of MCP-1 may drive the colonisation of disseminated breast cancer cells in the bone. Summary There is mounting evidence to suggest a pivotal role of MCP-1 in many diseases and an important role in the establishment of comorbidities. Coupled with its role in bone remodelling and the regulation of bone turnover, there is the potential for pathological relationships between bone disorders and bone-related cancers driven by MCP-1. MCP-1’s role in bone remodelling and bone-related cancers highlights its potential as a novel anti-resorptive and anti-metastatic target.

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The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures.

Journal of Experimental Medicine ◽

10.1084/jem.183.6.2581 ◽

1996 ◽

Vol 183 (6) ◽

pp. 2581-2591 ◽

Cited By ~ 149

Author(s):

E Romas ◽

N Udagawa ◽

H Zhou ◽

T Tamura ◽

M Saito ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Cells ◽

Osteoclast Formation ◽

Pcr Analysis ◽

Dihydroxyvitamin D3 ◽

Bone Marrow Cultures ◽

Primary Osteoblasts ◽

Marrow Cultures

Interleukin (IL)-11 is a multifunctional cytokine whose role in osteoclast development has not been fully elucidated. We examined IL-11 production by primary osteoblasts and the effects of rat monoclonal anti-mouse glycoprotein 130 (gp130) antibody on osteoclast formation, using a coculture of mouse osteoblasts and bone marrow cells. IL-1, TNF alpha, PGE2, parathyroid hormone (PTH) and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) similarly induced production of IL-11 by osteoblasts, but IL-6, IL-4, and TGF beta did not. Primary osteoblasts constitutively expressed mRNAs for both IL-11 receptor (IL-11R alpha) and gp130. Osteotropic factors did not modulate IL-11R alpha mRNA at 24 h, but steady-state gp130 mRNA expression in osteoblasts was upregulated by 1 alpha,25(OH)2D3, PTH, or IL-1. In cocultures, the formation of multinucleated osteoclast-like cells (OCLs) in response to IL-11, or IL-6 together with its soluble IL-6 receptor was dose-dependently inhibited by rat monoclonal anti-mouse gp130 antibody. Furthermore, adding anti-gp130 antibody abolished OCL formation induced by IL-1, and partially inhibited OCL formation induced by PGE2, PTH, or 1 alpha,25(OH)2D3. During osteoclast formation in marrow cultures, a sequential relationship existed between the expression of calcitonin receptor mRNA and IL-11R alpha mRNA. Osteoblasts as well as OCLs expressed transcripts for IL-11R alpha, as indicated by RT-PCR analysis and in situ hybridization. These results suggest a central role of gp130-coupled cytokines, especially IL-11, in osteoclast development. Since osteoblasts and mature osteoclasts expressed IL-11R alpha mRNA, both bone-forming and bone-resorbing cells are potential targets of IL-11.

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Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

International Journal of Molecular Sciences ◽

10.3390/ijms21082745 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2745

Author(s):

Yukihiro Kohara ◽

Ryuma Haraguchi ◽

Riko Kitazawa ◽

Yuuki Imai ◽

Sohei Kitazawa

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Signaling Pathway ◽

Early Stage ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Age Related ◽

Hh Signaling

The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine (smoothened (Smo) inhibitor), GANT-58 (GLI1 inhibitor), or GANT-61 (GLI1/2 inhibitor) significantly inhibited RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Although the inhibitory effects were exerted by cyclopamine or GANT-61 treatment during 0–48 h (early stage of osteoclast differentiation) or 48–96 h (late stage of osteoclast differentiation) after RANKL stimulation, GANT-58 suppressed osteoclast formation only during the early stage. These results suggest that the Smo-GLI1/2 axis mediates the whole process of osteoclastogenesis and that GLI1 activation is requisite only during early cellular events of osteoclastogenesis. Additionally, macrophage/osteoclast-specific deletion of Smo in mice was found to attenuate the aging phenotype characterized by trabecular low bone mass, suggesting that blockage of the Hh-signaling pathway in the osteoclast lineage plays a protective role against age-related bone loss. Our findings reveal a specific role of the Hh-signaling pathway in bone resorption and highlight that its inhibitors show potential as therapeutic agents that block osteoclast formation in the treatment of senile osteoporosis.

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CCR3 deficiency is associated with increased osteoclast activity and reduced cortical bone volume in adult male mice

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015571 ◽

2020 ◽

pp. jbc.RA120.015571

Author(s):

Sara Rosendahl ◽

Rima Sulniute ◽

Michaela Eklund ◽

Cecilia Koskinen Holm ◽

Marcus J. O. Johansson ◽

...

Keyword(s):

Mrna Expression ◽

Cortical Bone ◽

Bone Remodeling ◽

Adult Male ◽

Chemokine Receptors ◽

Osteoclast Formation ◽

Male Mice ◽

Primary Mouse ◽

Deficient Mice

Increasing evidence emphasizes the importance of chemokines and chemokine receptors as regulators of bone remodeling. The C-C chemokine receptor 3 (CCR3) is dramatically up-regulated during osteoclastogenesis but the role of CCR3 in osteoclast formation and bone remodeling in adult mice is unknown. Herein, we used bone marrow macrophages (BMM) derived from adult male CCR3-proficient and -deficient mice to study the role of CCR3 in osteoclast formation and activity. CCR3 deficiency was associated with formation of giant hypernucleated osteoclasts, enhanced bone resorption when cultured on bone slices and altered mRNA expression of related chemokine receptors and ligands. Additionally, primary mouse calvarial osteoblasts isolated from CCR3-deficient mice showed increased mRNA expression of the osteoclast activator related gene, receptor activator of nuclear factor kappa-B ligand (Rankl), and osteoblast differentiation associated genes. Micro-computed tomography analyses of femurs from CCR3-deficient mice revealed a bone phenotype that entailed less cortical thickness and volume. Consistent with our in vitro studies, the number of osteoclasts did not differ between the genotypes in vivo. Moreover, an increased endo-cortical osteoid mineralization rate and higher trabecular and cortical bone formation rate was displayed in CCR3-deficient mice. Collectively, our data show that CCR3 deficiency influences osteoblast and osteoclast differentiation and that it is associated with thinner cortical bone in adult male mice.

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