GDF15 Promotes the Osteogenic Cell Fate of Periodontal Ligament Fibroblasts, thus Affecting Their Mechanobiological Response

Abstract

Periodontal ligament fibroblasts (PdLFs) exert important functions in oral tissue and bone remodeling following mechanical forces, which are specifically applied during orthodontic tooth movement (OTM). Located between the teeth and the alveolar bone, mechanical stress activates the mechanomodulatory functions of PdLFs including regulating local inflammation and activating further bone-remodeling cells. Previous studies suggested growth differentiation factor 15 (GDF15) as an important pro-inflammatory regulator during the PdLF mechanoresponse. GDF15 exerts its effects through both intracrine signaling and receptor binding, possibly even in an autocrine manner. The extent to which PdLFs are susceptible to extracellular GDF15 has not yet been investigated. Thus, our study aims to examine the influence of GDF15 exposure on the cellular properties of PdLFs and their mechanoresponse, which seems particularly relevant regarding disease- and aging-associated elevated GDF15 serum levels. Therefore, in addition to investigating potential GDF15 receptors, we analyzed its impact on the proliferation, survival, senescence, and differentiation of human PdLFs, demonstrating a pro-osteogenic effect upon long-term stimulation. Furthermore, we observed altered force-related inflammation and impaired osteoclast differentiation. Overall, our data suggest a major impact of extracellular GDF15 on PdLF differentiation and their mechanoresponse.

GDF15 Modulates the Zoledronic-Acid-Induced Hyperinflammatory Mechanoresponse of Periodontal Ligament Fibroblasts

“…In this regard, a potential stress-signaling connection between both extrinsic influences already seems very likely for the TGF-β family in other cellular contexts [88]. We recently identified ALK1/2/5 as potential GDF15 receptors in hPdLFs [16], which are well described as acting in the SMAD signaling pathway. However, despite the functions of the mature secreted form of GDF15, intracellular activities of the immature GDF15 protein are also described [89].…”

“…GDF15 is a member of the TGFβ/BMP superfamily and is released by various cell types and tissues during metabolic, mechanical or chemical stress [18][19][20][21][22]. Consistently, GDF15 is also up-regulated by the mechanical stimulation of human periodontal ligament fibroblasts (hPdLFs), and promotes their pro-inflammatory response [2,16,17,23]. In addition to modulating osteogenic cell differentiation and inflammation in the PdL, GDF15 is also involved in the regulation of cell death and cellular senescence, as well as aging [2,15,16,19,24,25].…”

“…To visualize the cytokine secretion of the stimulated hPdLFs, activation of the monocytic THP1 cells was performed like previously described [16,49,50,52]. Briefly, Celltracker CMFDA (15 µM, 30 min, Thermo Fisher Scientific, Carlsbad, CA, USA)-stained nonadherent THP1 cells were applied for 30 min to the hPdLFs cultured on the coverslips.…”

“…TRAP staining was performed to analyze the hPdLF-modulated osteoclast activation as previously described [16]. Briefly, the THP1 cells were pre-stimulated with phorbol 12-myristate 13-acetate (PMA, 100 ng/mL) for macrophage differentiation prior to exposure to the supernatant of stimulated hPdLF medium for six days.…”

“…Recent studies by our group and Li et al have reported that also growth/differentiation factor 15 (GDF15) plays a major role in OTM [15][16][17]. GDF15 is a member of the TGFβ/BMP superfamily and is released by various cell types and tissues during metabolic, mechanical or chemical stress [18][19][20][21][22].…”