Histone hypo-acetylation of Sox9 mediates nicotine-induced weak cartilage repair by suppressing BMSC chondrogenic differentiation

Abstract

BackgroundNicotine has negative effects on tissue repair, little research concerns its effect on the cartilage repair of tissue engineering stem cells. The present study aimed to investigate the effects of nicotine on the bone marrow-derived mesenchymal stem cells’ (BMSCs) chondrogenic repair function of cartilage defects and explored the molecular mechanism.MethodsA cartilage defect model of rat was repaired by BMSC transplantation, and treated with nicotine or saline at 2.0 mg/kg/d in 12 weeks. Nicotine’s effect on chondrogenic differentiation was studied by exposing BMSCs to nicotine at 0.1, 1, 10, and 100 μM, and methyllycaconitine (MLA), which is a selective α7-nicotinic acetylcholine receptor (nAChR) inhibitor and si-RNA of nuclear factor of activated T cells 2 (NFATc2), were used to verify the molecular mechanism of nicotine’s effect.ResultsData showed that nicotine inhibited cartilage repair function by suppressing SRY-type high-mobility group box 9 (Sox9) in regenerated tissues. Further in vitro study demonstrated that nicotine enhanced intracellular Ca2+ and activity of calcineurin (CaN) through α7-nAChR, increased the nucleic expressions of NFATc2 and the bindings to SOX9 promoter, and thus reduced the acetylation of H3K9 and H3K14 in SOX9 promoter.ConclusionsFindings from this study demonstrated that nicotine suppressed the chondrogenic differentiation of BMSCs in vivo and in vitro, which offers insight into the risk assessment of cartilage defect repair in a nicotine exposure population and its therapeutic target.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0853-x) contains supplementary material, which is available to authorized users.

Association of Nicotine with Osteochondrogenesis and Osteoarthritis Development: The State of the Art of Preclinical Research

“…After the removal of duplicates, 472 articles fulfilled the inclusion criteria (Figure 1). After screening of their titles, abstracts, and full texts with the aforementioned criteria, 16 articles were finally included: 14 in vitro studies regarding effects of nicotine or smoke extract on MSCs osteochondrogenesis (Table S1) [9,19,20,21,22,23,24,25], osteoblast differentiation (Table S2) [26,27], and chondrocyte proliferation (Table S3) [7,12,17,28] and six animal studies regarding the effects of nicotine on osteochondral repair [9] and OA progression (Table S4) [12,15] and the outcomes of PNE on cartilage formation [28] and OA susceptibility in the offspring (Table S5) [17,29].…”

“…Osteoarthritis (OA) and focal (osteo-)chondral defects caused by trauma or osteochondral diseases, such as osteochondritis dissecans are often debilitating conditions chiefly affecting the articular cartilage, besides the subchondral bone and all other tissues forming diarthrodial joints [2,3,4]. Nicotine, the principal pharmacologically active component of smoking tobacco, smokeless tobacco, and e-cigarettes, has been long recognized as an important influencer of cartilage formation and OA [5,6,7,8,9].…”

“…Although many musculoskeletal conditions are complicated and adversely affected by cigarette smoking, including fracture repair and osteoporosis, spinal fusion, and degenerative disc disease, divergent data exist on the precise effects of nicotine on osteochondrogenesis and OA development due to the diversity of previous evidence from both preclinical and clinical trials [10,11,12,13,14]. For example, several epidemiological studies support the hypothesis that smoking may prevent OA [5,6,12,15,16]; however, preclinical studies indicate that prenatal nicotine exposure (PNE) suppressed insulin-like growth factor I (IGF-I) expression in fetal articular chondrocytes and down-regulated the chondrogenic differentiation of bone marrow-derived mesenchymal stem cells [9,17]. In the following, the term “medicinal signaling cells” (MSCs) will be used when referring to either mesenchymal stem or stromal cells [18].…”

LncRNA HOXA‐AS2 positively regulates osteogenesis of mesenchymal stem cells through inactivating NF‐κB signalling

“…The differentiation of MSCs can be regulated by specific growth factors, signalling molecules and epigenetic modifiers. More importantly, a number of phenotypic transcription factors were identified to regulate lineage commitment of MSCs, such as PPARγ and C/EBPα are involved in adipogenic differentiation, RUNX2 and SP7 contribute to the osteogenesis, Sox9 is a chondrogenic regulator …”

“…number of phenotypic transcription factors were identified to regulate lineage commitment of MSCs, such as PPARγ and C/EBPα are involved in adipogenic differentiation, [4][5][6] RUNX2 and SP7 contribute to the osteogenesis, [7][8][9] Sox9 is a chondrogenic regulator. [10][11][12] Inflammatory response is widely implicated in multiple cellular processes, such as proliferation, apoptosis and differentiation. [13][14][15][16][17] It is reported inflammation is significantly associated with osteogenic differentiation of MSCs.…”