Elsevier

Medical Hypotheses

Volume 79, Issue 6, December 2012, Pages 757-760
Medical Hypotheses

Combined therapeutic application of mTOR inhibitor and vitamin D3 for inflammatory bone destruction of rheumatoid arthritis

https://doi.org/10.1016/j.mehy.2012.08.022Get rights and content

Abstract

Inflammatory bone destruction is a prominent feature and a cause of substantial morbidity in several inflammatory diseases, including rheumatoid arthritis (RA), periodontitis, and peri-prosthetic loosening. Osteoclasts are unique, multinucleated giant cells that effectively resorb bone and thus are directly responsible for bone destruction in several inflammatory diseases. PI3K/Akt/mTOR pathway has been well known to play important roles in regulating adaptive and innate immune cell function. In addition to play roles in immune responses, several lines of evidence demonstrate that PI3K/Akt/mTOR pathway is critical for osteoclast differentiation and survival. These results suggest that inhibition of PI3K/Akt/mTOR pathway could protect against bone destruction in inflammatory diseases, including RA. However, the clinical use of mTOR inhibitors may be hampered due to limited clinical efficacy and frequent toxic side effects. In the treatment of RA, combination therapy with various disease-modifying antirheumatic drugs (DMARDs) has been suggested to improve the therapeutic efficacy and limit the side effects. In this report, we show several experimental evidences that vitamin D3 modulates mTOR pathway, and present a hypothesis that the combination of mTOR inhibitor and vitamin D3 can effectively inhibit osteoclast differentiation and function in chronic inflammatory condition such as RA, therefore this combination will be a powerful therapeutic regimen in preventing the inflammation-induced bone destruction in RA.

Introduction

Inflammatory osteolysis is a prominent feature and a cause of substantial morbidity in several inflammatory diseases such as rheumatoid arthritis (RA), periodontitis, and peri-prosthetic loosening. The most important consequence of inflammation adjacent to bone is the generation of osteoclasts that effectively resorbs bone and thus is directly responsible for bone destruction and morbidity in several inflammatory diseases [1]. Biologic agents designed to inhibit specific molecules involved in the pathogenesis of RA including cytokines such as TNFα and IL-1β have been shown to inhibit the progression of radiographic bone destruction in RA patients [2]. Treatment with TNF inhibitors in RA patients was shown to significantly inhibit bone loss, but bone loss of patients treated with TNF inhibitors was not completely arrested and continued during treatment [3]. Therefore, new therapeutic agent for bone loss of RA will be required.

Osteoclasts are multinucleated giant cells that are differentiated from hematopoietic cells of myeloid lineage [4]. Receptor activator of NF-κB ligand (RANKL) and M-CSF are essential molecules for differentiation of osteoclast from their precursors. These osteoclastogenic molecules are abundantly expressed in the inflammatory conditions such as RA. The role of osteoclast in inflammatory bone destruction has been intensively studied in experimental models of arthritis. Mouse models with genetic inhibition in osteoclast formation, such as c-fos knockout mice or mice deficient in either RANKL or RANK develop arthritis but do not exhibit bone erosion [5]. Cohens et al. showed that the addition of twice-yearly injections of denosumab (a fully human monoclonal antibody that binds and inhibits RANKL) to ongoing treatment with methotrexate inhibits structural damage, improves bone mineral density (BMD), and suppresses bone turnover in RA patients [6]. These results have shown that osteoclasts are essential for bone destruction in inflammatory condition and inhibition of osteoclast differentiation can be a very useful approach for treatment of inflammatory bone destruction. In inflammatory conditions, several molecules, such as TLR ligands, TNFα, IL-17, and prostaglandins stimulate osteoclast differentiation. The role of these inflammatory molecules on osteoclastogenesis is an attractive explanation for the influence of these molecules on bone structure and the high efficacy of biologic agents in the protection of bone structure in patients with RA [7]. However, this anti-osteoclastogenic effect of biologic agents is not enough to arrest completely the progression of inflammatory bone loss in RA.

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays important roles in regulating functions of the innate and adaptive immune response [8]. The mTOR pathway is activated by a variety of different stimuli via specific receptors, including T cell receptor (TCR), B cell receptor (BCR), various cytokine receptors and Toll-like receptors (TLRs). Engagement of the receptors triggers the recruitment of phosphoinositide 3-kinases (PI3K) and activates the downstream target molecules including serine/threonine kinase Akt [8]. Active Akt phosphorylates and inactivates the tuberous sclerosis complex protein 2 (TSC2), leading to a loss of suppression of mTOR by the TSC1–TSC2 complex. Active mTOR regulates protein translation by activating the p70 ribosomal protein S6 kinase (p70S6K) and inhibiting the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Recently, the factors essential for osteoclast differentiation and activation including M-CSF, RANKL and TNFα was reported to activate the mTOR pathway for promoting osteoclast survival [9], [10].

Due to critical roles of mTOR in regulating functions of the innate and adaptive immune response, mTOR inhibitors including sirolimus and everolimus are used for prevention of transplant rejection. In addition to prevention of transplant rejection, mTOR inhibition has been suggested as a promising therapeutic strategy for the treatment of autoimmune diseases such as type I diabetes, systemic lupus erythematosus and arthritis [11]. In addition to important roles of mTOR pathway in these autoimmune diseases, several evidences suggest that mTOR pathway may be involved in the pathogenesis of RA. In collagen-induced arthritis (CIA) mouse model of RA and adjuvant arthritis rat model, mTOR inhibitor rapamycin was reported to inhibit the clinical and histopathologic severity in a dose-dependent manner [12]. Also, in human TNF transgenic mouse model of arthritis, 2 different mTOR inhibitors protected against local bone erosion and cartilage loss as well as improving clinical signs of arthritis [13]. In this report, mTOR signaling activity was shown to be highly active in synovial tissue from patients with RA, especially in synovial osteoclast. In synovial fibroblast of RA patients, rapamycin inhibited growth factor-induced fibroblast proliferation and reduced the invasive properties of fibroblast via inhibition of actin reorganization and lamellipodia formation [14], [15]. In addition, recent report showed that IL-17 induces the proliferation of fibroblast derived from patients with RA and this proliferation is mediated through the mTOR pathway [16]. These findings provide the possibility that mTOR inhibitors may become important therapeutic agents in RA. However, until the present, only one clinical trial of mTOR inhibitor in RA patients has been published [17]. In this report, everolimus in combination with methotrexate was shown to provide only moderate clinical benefit and everolimus-treated patients experience a higher incidence of adverse events. Therefore, for using mTOR inhibitors as therapeutic agents of RA, the therapeutic efficacy and safety profile of mTOR inhibitor have to be improved.

In addition to play important roles in immune functions, several lines of evidence demonstrate that PI3K/Akt/mTOR pathway is critical for osteoclast differentiation and survival. In human TNF transgenic mouse model of arthritis, inhibition of mTOR pathway by sirolimus or everolimus was reported to reduce the formation of synovial osteoclast in inflamed joints [13]. In addition, osteoclast viability and osteoclast precursor proliferation was shown to be dependent on activation of mTOR pathway. Anti-apoptotic effect involving mTOR/S6K pathway is engaged in osteoclasts by osteoclastogenic cytokines including M-CSF, RANKL and TNFα, therefore inhibition of mTOR pathway by rapamycin induces apoptosis in osteoclast and suppresses in vitro bone resorption [9]. M-CSF-stimulated mTOR signaling induces anti-apoptotic action through inhibiting expression of pro-apoptotic molecule Bim in osteoclast precursors and deletion of mTOR protein by small interfering RNA (siRNA) gene silencing promotes apoptosis in osteoclast precursors [10]. In an ovariectomized (OVX) rat model, everolimus inhibits bone resorption by osteoclasts via inhibited expression of cathepsin K, the major collagen-degrading protease of osteoclasts responsible for the degradation of the organic bone matrix [18].

Section snippets

Hypotheses

In this report, we present a hypothesis that mTOR inhibitor will be a highly effective therapeutic molecule for preventing the osteoclast-induced structural damage in RA. Previous findings strongly suggest the possibility that mTOR inhibition effectively suppresses osteoclast-mediated bone erosion and joint destruction in arthritis [9], [10], [13], [18]. Until now, only one clinical trial of mTOR inhibitor in RA patients has been published that mTOR inhibitor provides an insufficient efficacy

Supporting evidences

Several clinical evidences showed that vitamin D3 deficiency has been linked to an increased incidence of autoimmune diseases and suggested that vitamin D3 supplementation might prevent the development of these diseases, thus providing the possibility that vitamin D3 may be used as an effective therapeutic agent in autoimmune disease [22], [23]. In addition to immune-regulatory properties of vitamin D3, recent experimental findings showed that vitamin D3 modulates PI3K/Akt/mTOR pathway and

Conclusions

Therapeutic application of mTOR inhibitor or vitamin D3 in inflammatory bone destructive disease such as RA is not new idea. However, until now, no clinical trial to apply this combined therapeutic regimen for bone destruction of RA has been published. If the hypothesis we suggested in this report is correct, a new, effective therapeutic strategy may be developed in the treatment of RA. In this report, we show several experimental evidences that vitamin D3 modulates mTOR pathway, and present a

Conflict of interest statement

None declared.

Acknowledgment

This study was supported by a Korea University Grant.

References (27)

  • S.B. Cohen et al.

    Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial

    Arthritis Rheum

    (2008)
  • G. Schett

    Erosive arthritis

    Arthritis Res Ther

    (2007)
  • H. Glantschnig et al.

    M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

    Cell Death Differ

    (2003)
  • Cited by (35)

    • Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis

      2021, Clinical Immunology
      Citation Excerpt :

      There is evidence that mTOR may be a target for RA and other autoimmune diseases. Since the PI3K/AKT/mTOR pathway is essential for the differentiation and survival of osteoclasts, the combination of mTOR inhibitors and vitamin D3 can prevent bone destruction in RA [95]. Moreover, mTOR inhibits the erosion of fibroblast-like synovial cells in the synovial tissue of RA patients [96].

    • MiR-650 inhibits proliferation, migration and invasion of rheumatoid arthritis synovial fibroblasts by targeting AKT2

      2017, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      AKT2 was also discovered to induce the expression of MMP13, IL36A and PGLYRP1 in RAFLSs, which then promoted the joint destruction [40]. Besides, the inhibition of PI3K/Akt/mTOR signaling could alleviate bone destruction in RA [41]. AKT is a critical element for the activation of mTOR signaling, which has been proved to be particularly active in synovial osteoclast membrane of RA patients and its inhibition could lead to low osteoclast apoptosis rate [42].

    • Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

      2016, International Journal of Biochemistry and Cell Biology
      Citation Excerpt :

      Indeed, it is well established that autophagy inducers limit ROS accumulation and oxidative stress by stimulating the autophagic degradation of ROS-generating mitochondria (Lee et al., 2012; Scherz-Shouval and Elazar, 2011). On the other hand, there is compelling evidence that antioxidant compounds, such as those indicated above, can induce autophagy, including statins (Andres et al., 2014; Wei et al., 2013; Zhang et al., 2013a), fasudil (Iorio et al., 2010), sulindac derivatives (Chiou et al., 2011; Gurpinar et al., 2013), and vitamin D3 (Hoyer-Hansen et al., 2010; Kim et al., 2012; Lisse and Hewison, 2011; Wu and Sun, 2011). Together with recent findings suggesting that the interplay between defective autophagy and redox imbalance may be integral to the development and progression of CCM lesions by sensitizing endothelial cells to local oxidative stress events (Marchi et al., 2015), these observations point to autophagy as a major redox-sensitive mechanism that justifies the reported effectiveness of the different potential therapeutic compounds described so far (Marchi et al., 2016a, b).

    • 1, 25(OH)<inf>2</inf>D<inf>3</inf> protects β cell against high glucose-induced apoptosis through mTOR suppressing

      2015, Molecular and Cellular Endocrinology
      Citation Excerpt :

      1, 25-Dihydroxyvitamin D3-3-bromoacetate, a vitamin D analog induces immunosuppression through PI3K/Akt/mTOR signaling cascade (Datta-Mitra et al., 2013). Combined applications of mTOR inhibitor and vitamin D3 add therapeutic effects for inflammatory bone destruction of rheumatoid arthritis (Kim et al., 2012). 1, 25(OH)2D3, when targeted on DNA-damage-inducible transcript 4 (DDIT4), an inhibitor of mTOR signaling, has the effect of suppressing cell proliferation in response to vitamin D (Lisse et al., 2011).

    View all citing articles on Scopus
    View full text