RANKL inhibition halts lesion progression and promotes bone remineralization in mice with fibrous dysplasia

Liu, Zhongyu; Yin, Yijia; Wang, Zheng; Xie, Liang; Deng, Peng; Wang, Donghui; Ji, Ning; Zhao, Hang; Han, Xianglong; Chen, Qianming; Chung, Chun-Hsi; Bai, Ding; Zhao, Xuefeng

doi:10.1016/j.bone.2021.116301

Cited by 14 publications

(17 citation statements)

References 45 publications

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“…Indeed, as patients age, the number of BMSCs bearing GNAS variants decreases, and the cellular composition of FD lesions normalizes (26) . We and others previously pointed to the importance of the cytokine RANKL in fibrous dysplasia (5) , and this lead to the development of targeted therapies, first in preclinical and compassionate treatment case studies (6,7,(27)(28)(29) and then in a clinical trial (8,9) , including ongoing studies (https://clinicaltrials.gov/study/NCT05419050). While early studies on the role of RANKL signaling in FD facilitated this promising therapeutic approach, little exploration has been done to find additional cytokines and factors secreted by FD BMSCs that may affect osteoclastic-osteoprogenitor crosstalk, as well as other important features of the FD pathogenesis, such as fibrous tissue deposition and remodeling, angiogenesis, and nociception.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, osteoclasts are recruited by an abnormally high production of RANKL by FD BMSCs, to the extent that circulating RANKL levels on FD patients average 16-fold increase that on healthy controls (5) . These findings led to the consideration of RANKL inhibition as a therapeutic approach for FD (6,7) . A clinical trial performed by our group using the anti-RANKL drug denosumab was shown successfully halt bone resorption in FD, and to prevent proliferation of altered BMSCs, leading to decreased cellularity, and normalized differentiation of affected BMSCs.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia

Michel,

Raborn,

Spencer

et al. 2024

Preprint

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Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in GNAS, encoding for Gαs, which leads to excessive cAMP signaling in bone marrow stromal cells (BMSCs). Despite advancements in our understanding of FD pathophysiology, the effect of Gαs activation in the BMSC transcriptome remains unclear, as well as how this translates into their local influence in the lesional microenvironment. In this study, we analyzed changes induced by Gαs activation in BMSC transcriptome and performed a comprehensive analysis of their production of cytokines and other secreted factors. We performed RNAseq of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, and combined their transcriptomic profiles to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. In addition, a comprehensive profile of their secreted cytokines and other factors was performed to identify modulation of several key factors we hypothesized to be involved in FD pathogenesis. We also screened circulating cytokines in a collection of plasma samples from patients with FD, finding positive correlations of several cytokines with their disease burden, as well as with other cytokines and bone turnover markers. Overall, these data support a pro-inflammatory, pro-osteoclastic behavior of BMSCs bearing hyperactive Gαs variants, and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia

Michel,

Raborn,

Spencer

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…Then, H&E staining was performed following the instructions of a staining kit (Solarbio). Tartrate‐resistant acid phosphatase (TRAP) staining was carried out as described by Liu et al 26 Osteoclasts, which were red‐marked multinucleated cells lining medullary space, were counted and divided by the area of alveolar bone in the low magnification field of view.…”

Section: Methodsmentioning

confidence: 99%

Periodontal ligament‐associated protein‐1 engages in teeth overeruption and periodontal fiber disorder following occlusal hypofunction

Chen

Luo

Xie

et al. 2022

J of Periodontal Research

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Background and Objective: Teeth overeruption is a problem of clinical significance, but the underlying mechanism how changes in external occlusal force convert to the periodontium remodeling signals has been a largely under explored domain. And recently, periodontal ligament-associated protein-1 (PLAP-1)/asporin was found to play a pivotal role in maintaining periodontal homeostasis. The aim of this study was to explore the function of PLAP-1 in the periodontally hypofunctional tissue turnover. Methods:After extracting left maxillary molars in mice, the left and right mandibular molars were distributed into hypofunction group (HG) and control group (CG), respectively. Mice were sacrificed for radiographic, histological, and molecular biological analyses after 1, 4 and 12 weeks. In vitro, dynamic compression was applied using Flexcell FX-5000 Compression System to simulate intermittent occlusal force. The expression of PLAP1 in loaded and unloaded human periodontal ligament cells (hP-DLCs) was compared, and its molecular biological effects were further explored by small interfering RNA (siRNA) targeting PLAP1. Results:In vivo, fiber disorder in periodontal ligament (PDL), bone apposition at furcation regions, and bone resorption in alveolar bone were illustrated in the HG compared with the CG. In addition, PLAP-1 positive area decreased significantly in PDL following occlusal unloading. In vitro, the loss of compressive loading relatively downregulated PLAP1 expression, which was essential to promote collagen I but inhibit osterix and osteocalcin expression in hPDLCs.Conclusions: PLAP-1 presumably plays a pivotal role in occlusal force-regulated periodontal homeostasis by facilitating collagen fiber synthesis in hPDLCs and suppressing excessive osteoblast differentiation, further preventing teeth from overeruption.

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“…In ovariectomized (OVX) mice, AS2690168 can inhibit the decrease in BMD in a dose-dependent manner without affecting the serum osteocalcin level. 194 In addition to osteoporosis, AS2676293 also shows a good therapeutic effect in rats with osteolytic diseases such as fibrous dysplasia 195 and bone metastasis. 196 Melagraki et al 197 constructed a computer virtual screening system based on structural modeling using known TNF inhibitors.…”

Section: Rankl Inhibitorsmentioning

confidence: 99%

Mechanistic advances in osteoporosis and anti‐osteoporosis therapies

Wang

Luo

Wang

et al. 2023

MedComm

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Osteoporosis is a type of bone loss disease characterized by a reduction in bone mass and microarchitectural deterioration of bone tissue. With the intensification of global aging, this disease is now regarded as one of the major public health problems that often leads to unbearable pain, risk of bone fractures, and even death, causing an enormous burden at both the human and socioeconomic layers. Classic anti‐osteoporosis pharmacological options include anti‐resorptive and anabolic agents, whose ability to improve bone mineral density and resist bone fracture is being gradually confirmed. However, long‐term or high‐frequency use of these drugs may bring some side effects and adverse reactions. Therefore, an increasing number of studies are devoted to finding new pathogenesis or potential therapeutic targets of osteoporosis, and it is of great importance to comprehensively recognize osteoporosis and develop viable and efficient therapeutic approaches. In this study, we systematically reviewed literatures and clinical evidences to both mechanistically and clinically demonstrate the state‐of‐art advances in osteoporosis. This work will endow readers with the mechanistical advances and clinical knowledge of osteoporosis and furthermore present the most updated anti‐osteoporosis therapies.

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RANKL inhibition halts lesion progression and promotes bone remineralization in mice with fibrous dysplasia

Cited by 14 publications

References 45 publications

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia

Periodontal ligament‐associated protein‐1 engages in teeth overeruption and periodontal fiber disorder following occlusal hypofunction

Mechanistic advances in osteoporosis and anti‐osteoporosis therapies

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