Fibroblast-secreted trophic factors contribute with ECM remodeling stimulus and upmodulate osteocyte gene markers in osteoblasts

doi:10.1016/j.biochi.2019.10.013

Biochimie

Volume 168, January 2020, Pages 92-99

https://doi.org/10.1016/j.biochi.2019.10.013 Get rights and content

Highlights

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Fibroblast-secreted factors promote osteocyte phenotype biomarkers expression in osteoblasts.
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Interleukins (ILs) and cytokines gene markers during fibroblast-induced osteoblast differentiation are changed.
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Fibroblast contributes to ECM remodeling stimulus in osteoblast behavior.

Abstract

As osteogenesis is a multifactorial mechanism, we wonder whether osteoblast-induced extracellular matrix (ECM) remodeling might be modulated by trophic factors released by fibroblasts in a paracrine signaling manner. To address this issue, fibroblasts were cultured for 72 h under conventional conditions when their conditioned medium was harvested and used to challenge pre-osteoblasts (MC3T3-E1 cells) for 14 days. Preliminarily, we validated the potential effect of fibroblasts in contributing to osteocyte phenotype, which specifically requires significant expression of Dentin Matrix Protein 1 (DMP1; about 10-fold changes) and Sclerostin (SOST; about 7-fold changes), both biomarkers of osteocyte. Fibroblasts also seem contributing to ECM remodeling in osteoblasts, because we detected a high level of both mRNA and enzyme activities of matrix metalloproteinase −9 (MMP-9) as well as a high level of reversion inducing cysteine rich protein with kazal motifs (RECK) transcripts (about 13-fold changes), a membrane-anchored MMP inhibitor, which seems to be a constitutive pathway in osteoblasts. Considering inflammatory panorama and using RTqPCR technology, both IL-13 (about 13-fold changes) and IL-33 (about 5-fold changes) genes were up-expressed in response to the fibroblast-secreted trophic factors, as were the receptor activator of NF-κB ligand (RANKL; about 8-fold changes) and osteoprotegerin (OPG; about 3-fold changes). Although preliminary, these data suggest a stimulus to finely control osteoclastogenesis, and this mechanism reinforces the role of fibroblasts in bone remodeling and homeostasis. Moreover, these results suggest an important crosstalk between fibroblast and osteoblast, when fibroblast-secreted trophic factors upmodulate osteocyte gene markers and contribute to ECM remodeling stimulus in osteoblast.

Graphical abstract

Introduction

Bone is a dynamic tissue undergoing constant remodeling to maintain skeletal properties [[1], [2], [3]]. Bone remodeling is responsible for repairing injured tissue by recruiting a multitude of synchronized cellular cues [4], mainly orchestrated by the balance of bone cells activities [5]. In this repairing tissue, the important role of immune cells-released inflammatory cytokines is known and highlights important crosstalk between the immune and skeletal systems [6], where extracellular matrix (ECM) plays a fundamental role in cellular anchorage and influences cell phenotype, as is shown for osteoblasts, osteoclasts, osteocytes, and fibroblasts [[7], [8], [9], [10]].

Thus, the ECM-related components decisively trigger specific metabolic pathways to regulate bone homeostasis. ECM remodeling requires efficient and finely regulated machinery, which involves a balance between matrix metalloproteinases (MMPs) and their natural inhibitors. Altogether, the MMP family can breakdown all of the ECM components, such as collagen fibers and gelatin, presenting collagenase and gelatinase activities, respectively. As documented in promoting ECM remodeling, MMPs are a driving mechanism in cell adhesion, migration, and differentiation in pathophysiological conditions [7,11], such as biological events driving ECM remodeling during osteoblastogenesis and osteoclastogenesis. We previously reported a strict control of ECM remodeling during ascorbate-induced osteoblast differentiation [12]. Thus, the coupling of ECM remodeling and components with osteoblast behavior is known to drive important mechanism during bone homeostasis, and its disruption might be involved with etiology and installation of bone disorders. In the bone microenvironment, bone marrow closely houses fibroblast and osteoblast, and crosstalk is expected to exist between them, even considering the relevance of fibroblast in secreting the majority of the organic components of ECM. More information is need to better understand if trophic factors released by fibroblasts might affect osteoblast activity.

Certainly, the dynamic homeostasis of bone tissue is guaranteed by the pleiotropic crosstalk involving paracrine-signaling of different cell lineages, as endothelial cells [13]. We recently introduced fibroblasts into this panorama [14]. Additionally, Wang et al. (2007) focused on the role of heterotypic cellular interactions in the fibrocartilage tissue to propose a biomimetic co-culture model considering osteoblast–fibroblast interactions and the relevance of these communications may lead to cell trans-differentiation and eventual fibrocartilage formation. Although genetically close to each other [15] and fibroblast has emerged as an interesting member mainly as a source of signaling trophic molecules able to modify surrounding cell phenotype, studies reporting the interplay between osteoblasts and fibroblasts are very scarce. Without considering cell-cell contact, to better understand the crosstalk between fibroblast and osteoblast, we challenged osteoblast cultures with fibroblast-released trophic factors by considering the conditioned medium of those cells. Moreover, although some progress has been made on this matter, the homeostasis of bone and related tissues seems to be a complex and dynamic mechanism involving heterotypic cellular interactions.

Therefore, we decided to better explore the behavior of pre-osteoblasts in response to trophic factors naturally-released by fibroblasts in vitro, considering a biological model as proposed previously [14]. In this study, our main focus was to understand whether fibroblasts are able to modulate osteoblast performance, mainly considering ECM remodeling and the repertory of genes related with osteogenic phenotype. Summarizing, our data indicate a dynamic crosstalk between fibroblast and osteoblast, where fibroblast contributes to osteoblast-related ECM remodeling, while genes listed with osteoblast-osteocyte transition (DMP-1 and SOST genes) were significantly activated. Briefly, our data suggest a molecular picture of fibroblast-released trophic factors that modify osteoblast biology, contributing to osteoblast-osteocyte transition and ECM remodeling.

Section snippets

Chemicals and primers

All chemicals were analytical grade and purchased from Sigma Co. (St. Louis, MO, USA). The primers were obtained from Exxtend Co. (Campinas, SP, Brazil).

Cells and culture condition

Pre-osteoblasts (MC3T3-E1, subclone 4) and fibroblasts (NIH-3T3-E1) were used in this study. The cells were maintained in incubator at 37 °C, 95% humidity, and 5% CO₂ in αMEM containing antibiotics (100 U/mL penicillin, 100 mg/mL streptomycin), Ribonucleosides and Deoxyribonucleotides, supplemented with 10% Fetal Bovine Serum (FBS) (Nutricell,

Results

To better address the possible involvement of fibroblast in osteoblast performance, fibroblasts were cultured for 72 h, when the conditioned medium was harvested to further treat pre-osteoblasts for 14 days [14] to allow biological analysis with zymography and qPCR technologies to identify eventual ECM remodeling and osteogenic stimulus in osteoblasts (Fig. 1, for the experimental design).

Discussion

Bone growth and healing comprise multifactorial mechanism requiring responses to a multitude of signals secreted by several cell types. The crosstalk between osteoblasts and endothelial cells was elegantly addressed by Kusumbe et al. (2014) who demonstrated the important role of endothelium in osteogenesis [13,27], opening new ways to understand the involvement of endothelial cells in osteoblast differentiation, which might be applied in bone healing mechanism. From studies by Ralf H. Adams,

Conclusions

In conjunction, our results indicate an important intercellular crosstalk between fibroblast and osteoblast, where fibroblast seems to contribute to osteoblast-osteocyte transition by up-expressing osteocyte gene markers and ECM remodeling in osteoblast. These findings contribute to better comprehension of bone tissue homeostasis.

Author contribution

Conception or design of the work: CJCF, WFZ; Data collection: CJCF; Data analysis and interpretation: CJCF, WFZ; Drafting the article: CJCF, WFZ; Critical revision of the article: WFZ; Final approval of the version to be published: CJCF, WFZ.

Acknowledgements

The authors are grateful to Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for the financial support (grants: #2016/08888-9; 2018/10856-3; 2014/22689-3).

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Research paperFibroblast-secreted trophic factors contribute with ECM remodeling stimulus and upmodulate osteocyte gene markers in osteoblasts

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemicals and primers

Cells and culture condition

Results

Discussion

Conclusions

Author contribution

Acknowledgements

Arch. Biochem. Biophys.

J. Biomech.

Bone

Bone

Injury

Prog Mol Biol Transl Sci

J. Biol. Chem.

Biochim. Biophys. Acta

Bone

Arch. Oral Biol.

Cell

Biochim. Biophys. Acta

Arch. Biochem. Biophys.

J. Investig. Dermatol.

Inflammation, mesenchymal stem cells and bone regeneration

Histochem. Cell Biol.

Development of secondary palate requires strict regulation of ECM remodeling: sequential distribution of RECK, MMP-2, MMP-3, and MMP-9

Cell Tissue Res.

Rat forming incisor requires a rigorous ECM remodeling modulated by MMP/RECK balance

J. Mol. Histol.

Expression of matrix metalloproteinases-2 and -9 and RECK during alveolar bone regeneration in rat

J. Mol. Histol.

Updating the role of matrix metalloproteinases in mineralized tissue and related diseases

J. Appl. Oral Sci.

Ascorbate-induced osteoblast differentiation recruits distinct MMP-inhibitors: RECK and TIMP-2

Mol. Cell. Biochem.

Corrigendum: coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone

Nature

Fibroblast contributes for osteoblastic phenotype in a MAPK-ERK and sonic hedgehog signaling-independent manner

Mol. Cell. Biochem.

Research paper
Fibroblast-secreted trophic factors contribute with ECM remodeling stimulus and upmodulate osteocyte gene markers in osteoblasts