Dataset Information

The Dopamine D1 Receptor Attenuates Titanium Particle-Induced Inhibition of Osteogenesis by Activating the Wnt Signaling Pathway.

ABSTRACT: Periprosthetic osteolysis (PPO), caused by wear particles, has become a major cause of joint replacement failure. Secondary surgery after joint replacement poses a serious threat to public health worldwide. Therefore, determining how to effectively inhibit wear particle-induced PPO has become an urgent issue. Recently, the interaction between osteogenic inhibition and wear particles at the biological interface of the implant has been found to be an important factor in the pathological process. Previous studies have found that the central nervous system plays an important role in the regulation of bone formation and bone remodeling. Dopamine (DA), an important catecholamine neurotransmitter, plays an integral role in the physiological and pathological processes of various tissues through its corresponding receptors. Our current study found that upregulation of dopamine first receptors could be achieved by activating the Wnt/β-catenin pathway, improving osteogenesis in vivo and in vitro, and significantly reducing the inhibition of titanium particle-induced osteogenesis. Overall, these findings suggest that dopamine first receptor (D1R) may be a plausible target to promote osteoblast function and resist wear particle-induced PPO.

SUBMITTER: Feng C

PROVIDER: S-EPMC9870688 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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The Dopamine D1 Receptor Attenuates Titanium Particle-Induced Inhibition of Osteogenesis by Activating the Wnt Signaling Pathway.

Feng Chengcheng C Li Yajun Y Gu Minhui M Li Wenming W Yang Yunshang Y Chen Shuangshuang S Ma Yong Y Geng Dechun D Xiao Long L Wang Zhirong Z

Mediators of inflammation 20230116

Periprosthetic osteolysis (PPO), caused by wear particles, has become a major cause of joint replacement failure. Secondary surgery after joint replacement poses a serious threat to public health worldwide. Therefore, determining how to effectively inhibit wear particle-induced PPO has become an urgent issue. Recently, the interaction between osteogenic inhibition and wear particles at the biological interface of the implant has been found to be an important factor in the pathological process. P ...[more]

PMID: 36700172

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Project description:BackgroundThe clinical healing environment after a posterior spinal arthrodesis surgery is one of the most clinically challenging bone-healing environments across all orthopedic interventions due to the absence of a contained space and the need to form de novo bone. Our group has previously reported that sclerostin in expressed locally at high levels throughout a developing spinal fusion. However, the role of sclerostin in controlling bone fusion remains to be established.MethodsWe computationally identified two FDA-approved drugs, as well as a single novel small-molecule drug, for their ability to disrupt the interaction between sclerostin and its receptor, LRP5/6. The drugs were tested in several in vitro biochemical assays using murine MC3T3 and MSCs, assessing their ability to (1) enhance canonical Wnt signaling, (2) promote the accumulation of the active (non-phosphorylated) form of β-catenin, and (3) enhance the intensity and signaling duration of BMP signaling. These drugs were then tested subcutaneously in rats as standalone osteoinductive agents on plain collagen sponges. Finally, the top drug candidates (called VA1 and C07) were tested in a rabbit posterolateral spine fusion model for their ability to achieve a successful fusion at 6 wk.ResultsWe show that by controlling GSK3b phosphorylation our three small-molecule inhibitors (SMIs) simultaneously enhance canonical Wnt signaling and potentiate canonical BMP signaling intensity and duration. We also demonstrate that the SMIs produce dose-dependent ectopic mineralization in vivo in rats as well as significantly increase posterolateral spine fusion rates in rabbits in vivo, both as standalone osteogenic drugs and in combination with autologous iliac crest bone graft.ConclusionsFew if any osteogenic small molecules possess the osteoinductive potency of BMP itself - that is, the ability to form de novo ectopic bone as a standalone agent. Herein, we describe two such SMIs that have this unique ability and were shown to induce de novo bone in a stringent in vivo environment. These SMIs may have the potential to be used in novel, cost-effective bone graft substitutes for either achieving spinal fusion or in the healing of critical-sized fracture defects.FundingThis work was supported by a Veteran Affairs Career Development Award (IK2-BX003845).

Project description:BackgroundForkhead box protein f1 (Foxf1) is associated with cell differentiation, and may be a key player in bone homoeostasis. However, the effect of Foxf1 on osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) and ovariectomy-induced bone loss, as well as its clinical implications, is unknown.MethodsBy quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, we assayed Foxf1 expression in bone tissue, BMSCs, and bone marrow-derived macrophages (BMMs), derived from ovariectomised (OVX) mice, and during osteogenic differentiation and osteoclast differentiation. Using a loss-of-function approach (small interfering RNA [siRNA]-mediated knockdown) in vitro, we examined whether Foxf1 regulates osteoblast differentiation of BMSCs via the Wnt/β-catenin signalling pathway. Furthermore, we assessed the anabolic effect of Foxf1 knockdown (siFoxf1) in OVX mice in vivo. We also assayed the expression of Foxf1 in bone tissue derived from postmenopausal osteoporosis (PMOP) patients and its link with bone mineral density (BMD). Finally, we examined the effect of Foxf1 knockdown on the osteoblastic differentiation of human BMSCs.FindingsFoxf1 expression was significantly increased in bone extract and BMSCs from OVX mice and gradually decreased during osteoblastic differentiation of BMSCs but did not differ significantly in OVX mouse-derived BMMs or during osteoclast differentiation. In vitro, Foxf1 knockdown markedly increased the expression of osteoblast specific genes, alkaline phosphatase (ALP) activity, and mineralisation. Moreover, siFoxf1 activated the Wnt/β-catenin signalling pathway. The siFoxf1-induced increase in osteogenic differentiation was partly rescued by inhibitor of Wnt signalling (DKK1). In OVX mice, Foxf1 siRNA significantly reduced bone loss by enhancing bone formation. Foxf1 expression levels negatively correlated with reduced bone mass and bone formation in bone tissue from PMOP patients. Finally, Foxf1 knockdown significantly promoted osteogenesis by human BMSCs.InterpretationOur findings indicate that Foxf1 knockdown promotes BMSC osteogenesis and prevents OVX-induced bone loss. Therefore, Foxf1 has potential as a biomarker of osteogenesis and may be a therapeutic target for PMOP.

Dataset Information

The Dopamine D1 Receptor Attenuates Titanium Particle-Induced Inhibition of Osteogenesis by Activating the Wnt Signaling Pathway.

Publications

The Dopamine D1 Receptor Attenuates Titanium Particle-Induced Inhibition of Osteogenesis by Activating the Wnt Signaling Pathway.

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