Chemokines and Bone

Gilchrist, Annette; Stern, Paula H.

doi:10.1007/s12018-015-9184-y

Cited by 9 publications

(3 citation statements)

References 200 publications

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“…Chemokines serve as ligands to the chemokine receptors which belong to the G-protein coupled receptor (GPCR) superfamily. The transmembrane, heptahelical proteins are primarily expressed on leukocytes but can also be found on several other cell types (26). Chemokine receptors are named based on the type of chemokine they bind.…”

Section: Chemokines and Chemokine Receptorsmentioning

confidence: 99%

“…Chemokines are a group of small proteins (8)(9)(10)(11)(12), best known for their ability to provide directional guidance to migrating cells. They also play a role in neural regeneration, angiogenesis, cell activation, proliferation and differentiation, and cancer metastasis (26,27). Chemokinereceptor 1 (CCR1) plays an extensive role in the bone microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Chemokine Receptor CCR1 as a Potential Therapeutic Approach for Multiple Myeloma

Gilchrist

Echeverria

2022

Front. Endocrinol.

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Multiple myeloma is an incurable plasma B-cell malignancy with 5-year survival rates approximately 10-30% lower than other hematologic cancers. Treatment options include combination chemotherapy followed by autologous stem cell transplantation. However, not all patients are eligible for autologous stem cell transplantation, and current pharmacological agents are limited in their ability to reduce tumor burden and extend multiple myeloma remission times. The “chemokine network” is comprised of chemokines and their cognate receptors, and is a critical component of the normal bone microenvironment as well as the tumor microenvironment of multiple myeloma. Antagonists targeting chemokine-receptor 1 (CCR1) may provide a novel approach for treating multiple myeloma. In vitro CCR1 antagonists display a high degree of specificity, and in some cases signaling bias. In vivo studies have shown they can reduce tumor burden, minimize osteolytic bone damage, deter metastasis, and limit disease progression in multiple myeloma models. While multiple CCR1 antagonists have entered the drug pipeline, none have entered clinical trials for treatment of multiple myeloma. This review will discuss whether current CCR1 antagonists are a viable treatment option for multiple myeloma, and studies aimed at identifying which CCR1 antagonist(s) are most appropriate for this disease.

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Section: Chemokines and Chemokine Receptorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting Chemokine Receptor CCR1 as a Potential Therapeutic Approach for Multiple Myeloma

Gilchrist

Echeverria

2022

Front. Endocrinol.

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“…Dioxin-treated cells also expressed lower levels of CCR6, which encodes the receptor for CCL20. This chemokine has many roles, including cell migration and enhancement of MMP3 expression (Gilchrist and Stern, 2015, Honczarenko et al, 2006). Given these roles, the inhibitory effect of dioxin on CCR6 may directly impact BMSC migration and chemotaxis.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation

et al. 2017

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While inhibition of bone healing and increased rates of pseudarthrosis are known adverse outcomes associated with cigarette smoking, the underlying mechanisms by which this occurs are not well understood. Recent work has implicated the Aryl Hydrocarbon Receptor (Ahr) as one mediator of the anti-osteogenic effects of cigarette smoke (CS), which contains numerous toxic ligands for the Ahr. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity Ahr ligand frequently used to evaluate Ahr pathway activation. The purpose of this study was to elucidate the downstream mechanisms of dioxin action on bone regeneration and investigate Ahr antagonism as a potential therapeutic approach to mitigate the effects of dioxin on bone. Markers of osteogenic activity and differentiation were assessed in primary rat bone marrow stromal cells (BMSC) after exposure to dioxin, Ahr antagonists, or antagonist + dioxin. Four Ahr antagonists were evaluated: α-Naphthoflavone (ANF), resveratrol (Res), 3,3′-Diindolylmethane (DIM), and luteolin (Lut). Our results demonstrate that dioxin inhibited ALP activity, migratory capacity, and matrix mineralization, whereas co-treatment with each of the antagonists mitigated these effects. Dioxin also inhibited BMSC chemotaxis, while co-treatment with several antagonists partially rescued this effect. RNA and protein expression studies found that dioxin down-regulated numerous pro-osteogenic targets, whereas co-treatment with Ahr antagonists prevented these dioxin-induced expression changes to varying degrees. Our results suggest that dioxin adversely affects bone regeneration in a myriad of ways, many of which appear to be mediated by the Ahr. Our work suggests that the Ahr should be investigated as a therapeutic target to combat the adverse effects of CS on bone healing.

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Retracted: Release of CXCL12 From Apoptotic Skeletal Cells Contributes to Bone Growth Defects Following Dexamethasone Therapy in Rats

Tang

Fan

et al. 2018

Journal of Bone and Mineral Research

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Dexamethasone (Dex) is known to cause significant bone growth impairment in childhood. Although previous studies have suggested roles of osteocyte apoptosis in the enhanced osteoclastic recruitment and local bone loss, whether it is so in the growing bone following Dex treatment requires to be established. The current study addressed the potential roles of chemokine CXCL12 in chondroclast/osteoclast recruitment and bone defects following Dex treatment. Significant apoptosis was observed in cultured mature ATDC5 chondrocytes and IDG-SW3 osteocytes after 48 hours of 10 À6 M Dex treatment, and CXCL12 was identified to exhibit the most prominent induction in Dex-treated cells. Conditioned medium from the treated chondrocytes/osteocytes enhanced migration of RAW264.7 osteoclast precursor cells, which was significantly inhibited by the presence of the anti-CXCL12 neutralizing antibody. To investigate the roles of the induced CXCL12 in bone defects caused by Dex treatment, young rats were orally gavaged daily with saline or Dex at 1 mg/kg/day for 2 weeks, and received an intraperitoneal injection of anti-CXCL12 antibody or control IgG (1 mg/kg, three times per week). Aside from oxidative stress induction systemically, Dex treatment caused reductions in growth plate thickness, primary spongiosa height, and metaphysis trabecular bone volume, which are associated with induced chondrocyte/ osteocyte apoptosis and enhanced chondroclast/osteoclast recruitment and osteoclastogenic differentiation potential. CXCL12 was induced in apoptotic growth plate chondrocytes and metaphyseal bone osteocytes. Anti-CXCL12 antibody supplementation considerably attenuated Dex-induced chondroclast/osteoclast recruitment and loss of growth plate cartilage and trabecular bone. CXCL12 neutralization did not affect bone marrow osteogenic potential, adiposity, and microvasculature. Thus, CXCL12 was identified as a potential molecular linker between Dex-induced skeletal cell apoptosis and chondroclastic/osteoclastic recruitment, as well as growth plate cartilage/bone loss, revealing a therapeutic potential of CXCL12 functional blockade in preventing bone growth defects during/after Dex treatment. CHEMOKINE CXCL12 IN DEX THERAPY-INDUCED BONE GROWTH DEFECTS 311 54. Ellies DL, Viviano B, McCarthy J, et al. Bone density ligand, sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J Bone Miner Res. 2006;21(11):1738-49. 55. Hosogane N, Huang Z, Rawlins BA, et al. Stromal derived factor-1 regulates bone morphogenetic protein 2-induced osteogenic differentiation of primary mesenchymal stem cells. Int J Biochem

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Chemokines and Bone

Cited by 9 publications

References 200 publications

Targeting Chemokine Receptor CCR1 as a Potential Therapeutic Approach for Multiple Myeloma

Targeting Chemokine Receptor CCR1 as a Potential Therapeutic Approach for Multiple Myeloma

Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation

Retracted: Release of CXCL12 From Apoptotic Skeletal Cells Contributes to Bone Growth Defects Following Dexamethasone Therapy in Rats

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