Review
Effect of TNFα on osteoblastogenesis from mesenchymal stem cells

https://doi.org/10.1016/j.bbagen.2013.12.013Get rights and content

Highlights

  • We review the mechanism of the effect of TNFα on osteoblastogenesis from MSC.

  • We highlight the function of MSC in the pathogenesis of autoimmune diseases.

  • TNFα inhibits osteoblastogenesis through several mechanisms.

  • An understanding of the role of TNFα on osteoblastogenesis leads to new therapies.

Abstract

Background

Bone destruction and osteoporosis are accelerated in chronic inflammatory diseases, such as rheumatoid arthritis (RA) and periodontitis, in which many studies have shown the proinflammatory cytokines, especially TNFα, play an important role; TNFα causes osteoclast-induced bone destruction as well as the inhibition of osteoblastogenesis.

Scope of review

Here we review our current understanding of the mechanism of the effect of TNFα on osteoblastogenesis from mesenchymal stem cells (MSCs). We also highlight the function of MSC in the pathogenesis of autoimmune diseases.

Major conclusions

Many studies have revealed that TNFα inhibits osteoblastogenesis through several mechanisms. On the other hand, it has been also reported that TNFα promotes osteoblastogenesis. These discrepancies may depend on the cellular types, the model animals, and the timing and duration of TNFα administration.

General significance

A full understanding of the role and function of TNFα on osteoblastogenesis from MSC may lead to targeted new therapies for chronic inflammation diseases, such as RA and periodontitis.

Introduction

Bone mineral density and bone strength are mainly determined by the balance between bone formation by osteoblasts and bone resorption by osteoclasts. Interestingly, osteoblasts are derived from mesenchymal stem cells, whereas osteoclasts are derived from monocytes or macrophages of hematopoietic lineage. Osteoclastogenesis is under the strict control of osteoblasts producing macrophage colony-forming units (M-CSF), receptor activator of NFκB ligand (RANKL), and osteoprotegerin (OPG) [1]. However, recent studies have shown that osteoblasts regulate osteoclastogenesis through mechanisms independent of M-CSF, RANKL, and OPG [2].

Bone destruction and osteoporosis are accelerated in chronic inflammatory diseases, such as rheumatoid arthritis (RA) and periodontitis, in which many studies have shown the proinflammatory cytokines, especially TNFα, play an important role [3], [4], [5]; TNFα causes osteoclast-induced bone destruction [6], [7], [8] as well as the inhibition of osteoblastogenesis. In the current review article, we focused on the mechanism of the effect of TNFα on osteoblastogenesis from mesenchymal stem cells.

Section snippets

Mesenchymal stem cells

In 1976, Friedenstein et al. first identified bone marrow (BM) stromal cells, describing an adherent fibroblast-like population able to differentiate into the bone that they referred to as osteogenic precursor cells [9]. BM-derived mesenchymal stem cells (MSCs) reside in BM stroma, providing the supporting feeder cells necessary for hematopoietic progenitor cell growth but they may also differentiate into connective tissue cells, such as osteoblasts, osteocytes, chondrocytes, adipocytes and

MSC in inflammatory-related bone diseases

Recently, a growing body of evidence has indicated that BMMSCs produce a variety of cytokines and display profound immunomodulatory properties, perhaps by inhibiting the proliferation and function of several major immune cells, such as natural killer cells, dendritic cells, and T and B lymphocytes [21].

Role of Wnt in osteoblastogenesis

Osteoblasts are derived from mesenchymal progenitor cells in the bone marrow or pericytes. Their maturation process includes consecutive stages of proliferation, matrix production and matrix mineralization [39]. Osteoblasts can ultimately become osteocytes. Activation of the Wingless-type MMTV integration site (Wnt) pathways facilitates osteoblast specification from mesenchymal progenitors and enhances bone mass and strength. Thus, the Wnt pathway has emerged as a crucial regulator of bone

RA and postmenopausal osteoporosis

The majority of studies of anti-TNFα therapies have focused on RA, and the positive effects of these therapies have been considered secondary to mitigation of the chronic inflammatory nature of RA. On the other hand, studies have shown that TNFα plays a central role in the pathophysiology of postmenopausal osteoporosis [33]. It is speculated that TNFα inhibits osteoblastogenesis by the mechanism as mentioned in Section 6. Although postmenopausal osteoporosis is a chronic inflammatory

TNF inhibits osteoblastogenesis

Previous studies have demonstrated the ability of TNFα to inhibit multiple osteoblast functions in vitro as well as fracture repair in vivo [42]. The signal-transduction pathways activated by TNFα binding to its receptors have been studied extensively in several systems [43]. In regard to TNFα effects on osteoblastogenesis in vitro, recent work using fetal rat calvarial cells and a murine calvarial osteoblastic cell line has demonstrated that TNFα (a) is a potent inhibitor of osteoblast

GSK3β is a checkpoint for TNFα-mediated impaired osteogenic differentiation of PDLSC

In the recent issue of BBA, Kong et al. reported that GSK3β is a checkpoint for TNFα-mediated impaired osteogenic differentiation of MSC in inflammatory microenvironments [5] (Fig. 2). Their findings demonstrated that in inflammatory microenvironments, TNFα induced the phosphorylation of GSK3β, and p-GSK3β subsequently resulted in nuclear β-catenin accumulation and β-catenin/Lef-1complex formation, which inhibited Runx2-associated osteogenesis of human periodontal ligament tissue-derived

Stimulatory effect of TNFα on osteogenesis

Hess et al. showed that TNFα increases BMP-2 expression in hMSC through the NFκB signaling pathway in early osteogenic differentiation [48]. NFκB stimulates critical regulators of osteogenesis such as BMP2, RUNX2, and Osterix and these events finally result in enhanced mineralization of the extracellular matrix.

Several earlier reports had suggested that TNFα is a negative regulator of osteoblast differentiation, as mentioned in Section 6. An important difference between the earlier studies and

Conclusions

Many studies have revealed that TNFα inhibits osteoblastogenesis through several mechanisms. On the other hand, it has been also reported that TNFα promotes osteoblastogenesis. These discrepancies may depend on the cellular types, the model animals, and the timing and duration of TNFα administration. To develop more effective therapies targeting TNFα, these mechanisms remain to be elucidated.

Conflict of interest

The authors declare that they have no conflicts of interest.

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