Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice

Donham, Cristine; Chicana, Betsabel; Robling, Alexander G.; Mohamed, Asmaa H.; Elizaldi, Sonny R.; Chi, Michael; Freeman, Brian M.; Millan, Alberto J.; Murugesh, Deepa K.; Hum, Nicholas R.; Sebastian, Aimy; Loots, Gabriela G.; Manilay, Jennifer O.

doi:10.3390/ijms22179111

Cited by 10 publications

(7 citation statements)

References 102 publications

(125 reference statements)

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“…SOST overexpression or administration of recombinant mouse SOST prevented AAA development [39,56]. Our study also established a new role for SOST in controlling aortic SMC phenotype modulation by reducing β-catenin nuclear translocation in addition to SOST's effects on inflammation [39,57,58]. Moreover, we showed that activation of the WNT singling using WNT agonist 1 upregulated KLF4 expression.…”

Section: Discussionsupporting

confidence: 57%

Colchicine Blocks Abdominal Aortic Aneurysm Development by Maintaining Vascular Smooth Muscle Cell Homeostasis

Chen,

Yang,

Zhou

et al. 2024

Int. J. Biol. Sci.

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Development of non-surgical treatment of human abdominal aortic aneurysm (AAA) has clinical significance. Colchicine emerges as an effective therapeutic regimen in cardiovascular diseases. Yet, whether colchicine slows AAA growth remain controversy. Here, we demonstrated that daily intragastric administration of low-dose colchicine blocked AAA formation, prevented vascular smooth muscle cell (SMC) phenotype switching and apoptosis, and vascular inflammation in both peri-aortic CaPO 4 injury and subcutaneous angiotensin-II infusion induced experimental AAA mice models. Mechanistically, colchicine increased global mRNA stability by inhibiting the METTL14/YTHDC1-mediated m6A modification, resulting in increased sclerostin (SOST) expression and consequent inactivation of the WNT/β-catenin signaling pathway in vascular SMCs from mouse AAA lesions and in cultured human aortic SMCs. Moreover, human and mouse AAA lesions all showed increased m6A methylation, decreased SOST expression, and skewed synthetic SMC de-differentiation phenotype, compared to those without AAA. This study uncovers a novel mechanism of colchicine in slowing AAA development by using the METTL14/SOST/WNT/β-catenin axis to control vascular SMC homeostasis in mouse aortic vessels and in human aortic SMCs. Therefore, use of colchicine may benefit AAA patients in clinical practice.

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Section: Discussionsupporting

confidence: 57%

Colchicine Blocks Abdominal Aortic Aneurysm Development by Maintaining Vascular Smooth Muscle Cell Homeostasis

Chen,

Yang,

Zhou

et al. 2024

Int. J. Biol. Sci.

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“…Studies on Sost −/− recipient mice have demonstrated for SOST an inhibitory effect on proliferation and mobilization of myeloid progenitor. These suppression mechanisms would involve lymphoid cell also [ 30 ] and potentially platelet count. A positive correlation between SOST levels and platelets count was indeed observed here.…”

Section: Discussionmentioning

confidence: 99%

Early sclerostin assessment in frail elderly patients with sepsis: insights on short- and long-term mortality prediction

et al. 2023

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Unmet needs challenge clinical management of sepsis especially concerning patient profiling, enhancing recovery, and long-term sequelae. Here, we preliminarily focused on sclerostin (SOST) as a candidate biomarker to encompass such a broad range of clinical needs related to sepsis. Seventy-three septic patients were enrolled at internal medicine wards between January 2017 and December 2019 in this pilot study. Clinical examination and blood sample analyses were collected at enrollment and after 7 and 14 days. SOST levels were assessed on serum by ELISA. Thirty-day mortality was set as primary outcome. In-hospital and long-term mortality (2.5 years of median follow-up) were assessed as secondary outcomes. Patients were frail, elderly, and heterogeneous in terms of comorbidity burden. SOST levels were associated with age, cardiovascular comorbidities, and time to early death (30 days). When regression models were built, SOST displayed a high predictive value toward 30-day mortality (OR 13.459 with 95% CI 1.226–148.017) with ever better performance than validated scoring scales for critical ill patients. Such a predictive value of SOST was further confirmed for in-hospital (HR 10.089 with 95% CI 1.375–74.013) and long-term mortality (HR 5.061 with 95% CI 1.379–18.570). SOST levels generally decreased over 7 to 14 days after enrollment (p for trend < 0.001). The degree of this variation further predicted long-term mortality (HR for Δ SOST T0–day 14: 1.006 with 95% CI 1.001–1.011). Our results suggest a role for SOST in both short- and long-time prediction of worse outcome in septic elderly admitted to internal medicine wards. Graphical abstract

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“…It has been observed that short-term depletion of sclerostin alters immune cell development in the BM and spleen. 147 In addition, depletion of sclerostin correlates with enhanced levels of inflammatory cytokines such as MCP-1, TNF-α, etc, 147 thereby, questioning the employment of sclerostin in postmenopausal osteoporotic patients. Thus, in search for a safe, novel, and cost-effective therapeutic strategy our group along with other’s have reported that probiotics exhibit immunoporotic potential, thereby enhancing bone health in several bone anomalies including osteoporosis.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

The Rising Era of “Immunoporosis”: Role of Immune System in the Pathophysiology of Osteoporosis

Srivastava¹,

Sapra²

2022

JIR

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Discoveries in the last few years have emphasized the existence of an enormous breadth of communication between bone and the immune system in maintaining skeletal homeostasis. Originally, the discovery of various factors was assigned to the immune system viz. interleukin (IL)-6, IL-10, IL-17, tumor necrosis factor (TNF)-α, receptor activator of nuclear factor kappa B ligand (RANKL), nuclear factor of activated T cells (NFATc1), etc., but now these factors have also been shown to have a significant impact on osteoblasts (OBs) and osteoclasts (OCs) biology. These discoveries led to an alteration in the approach for the treatment of several bone pathologies including osteoporosis. Osteoporosis is an inflammatory bone anomaly affecting more than 500 million people globally. In 2018, to highlight the importance of the immune system in the pathophysiology of osteoporosis, our group coined the term “immunoporosis”. In the present review, we exhaustively revisit the characteristics, mechanism of action, and function of both innate and adaptive immune cells with the goal of understanding the potential of immune cells in osteoporosis. We also highlight the Immunoporotic role of gut microbiota (GM) for the treatment and management of osteoporosis. Importantly, we further discuss whether an immune cell-based strategy to treat and manage osteoporosis is feasible and relevant in clinical settings.

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Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice

Cited by 10 publications

References 102 publications

Colchicine Blocks Abdominal Aortic Aneurysm Development by Maintaining Vascular Smooth Muscle Cell Homeostasis

Colchicine Blocks Abdominal Aortic Aneurysm Development by Maintaining Vascular Smooth Muscle Cell Homeostasis

Early sclerostin assessment in frail elderly patients with sepsis: insights on short- and long-term mortality prediction

The Rising Era of “Immunoporosis”: Role of Immune System in the Pathophysiology of Osteoporosis

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