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1.
Bone Res ; 12(1): 52, 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39231935

ABSTRACT

Osteoporosis remains incurable. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation, while the anabolic agent, teriparatide, does not inhibit bone resorption, and thus they have limited efficacy in preventing osteoporotic fractures and cause some side effects. Thus, there is an unmet need to develop dual antiresorptive and anabolic agents to prevent and treat osteoporosis. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited marrow fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.


Subject(s)
Bone Density Conservation Agents , Bone Resorption , Diphosphonates , Hydroxychloroquine , Ovariectomy , Animals , Ovariectomy/adverse effects , Female , Mice , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Diphosphonates/pharmacology , Diphosphonates/therapeutic use , Bone Resorption/prevention & control , Bone Resorption/drug therapy , Bone Resorption/metabolism , Bone Density Conservation Agents/pharmacology , Bone Density Conservation Agents/therapeutic use , Mice, Inbred C57BL , Anabolic Agents/pharmacology , Anabolic Agents/therapeutic use , Osteogenesis/drug effects , Osteoporosis/drug therapy , Osteoporosis/prevention & control , Osteoporosis/metabolism , Osteoporosis/pathology , Osteoclasts/drug effects , Osteoclasts/metabolism
2.
Cancer Immunol Immunother ; 73(10): 203, 2024 Aug 06.
Article in English | MEDLINE | ID: mdl-39105847

ABSTRACT

BACKGROUND: Chimeric antigen receptor (CAR)-T cells have been used to treat blood cancers by producing a wide variety of cytokines. However, they are not effective in treating solid cancers and can cause severe side-effects, including cytokine release syndrome. TNFα is a tumoricidal cytokine, but it markedly increases the protein levels of cIAP1 and cIAP2, the members of inhibitor of apoptosis protein (IAP) family of E3 ubiquitin ligase that limits caspase-induced apoptosis. Degradation of IAP proteins by an IAP antagonist does not effectively kill cancer cells but enables TNFα to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNFα through an inactive adoptive cell in combination with an IAP antagonist. METHODS: Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNFα, and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNFα (M-DCsTNF). The efficacy of M-DCsTNF in recognizing and treating breast cancer was tested in vitro and in vivo. RESULTS: Mucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCsTNF directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCsTNF plus an IAP antagonist, SM-164, but neither alone, markedly induce MDA-MB-231 breast cancer cell apoptosis, which was blocked by TNF antibody. Importantly, M-DCsTNF combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice. CONCLUSION: An adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome.


Subject(s)
Dendritic Cells , Receptors, Chimeric Antigen , Tumor Necrosis Factor-alpha , Humans , Animals , Mice , Dendritic Cells/immunology , Dendritic Cells/metabolism , Female , Receptors, Chimeric Antigen/immunology , Tumor Necrosis Factor-alpha/metabolism , Mucin-1/immunology , Mucin-1/metabolism , Xenograft Model Antitumor Assays , Cell Line, Tumor , Inhibitor of Apoptosis Proteins/antagonists & inhibitors , Inhibitor of Apoptosis Proteins/metabolism , Immunotherapy, Adoptive/methods , Apoptosis , Breast Neoplasms/therapy , Breast Neoplasms/immunology , Immunotherapy/methods , Neoplasms/therapy , Neoplasms/immunology , Mice, SCID
3.
JBMR Plus ; 8(7): ziae070, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38868596

ABSTRACT

The International Society of Bone Morphometry (ISBM) is dedicated to advancing research, education, and clinical practice for osteoporosis and other bone disorders by developing and improving tools for the quantitative imaging and analysis of bone. Its initial core mission was to promote the proper use of morphometric techniques in bone research and to educate and train clinicians and basic scientists in bone morphometry. This article chronicles the evolution of the ISBM and the history and development of bone morphometric techniques for the past 50-years, starting with workshops on bone morphometry in 1973, to the formal incorporation of the ISBM in 1996, to today. We also provide a framework and vision for the coming decades. This effort was led by ISBM presidents Dr Erica L. Scheller (2022-2024) and Dr Thomas J. Wronski (2009-2012) in collaboration with all other living ISBM presidents. Though the underlying techniques and questions have changed over time, the need for standardization of established tools and discovery of novel approaches for bone morphometry remains a constant. The ISBM fulfills this need by providing a forum for the exchange of ideas, with a philosophy that encourages the open discussion of pitfalls and challenges among clinicians, scientists, and industry partners. This facilitates the rapid development and adaptation of tools to meet emerging demands within the field of bone health at a high level.

4.
Res Sq ; 2024 May 03.
Article in English | MEDLINE | ID: mdl-38746138

ABSTRACT

Osteoporosis is incurable because there are no dual antiresorptive and anabolic therapeutic agents that can be administered long-term. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation and thus have limited effect in preventing osteoporotic fracture. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.

5.
Bone Res ; 12(1): 10, 2024 02 20.
Article in English | MEDLINE | ID: mdl-38378678

ABSTRACT

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191.


Subject(s)
Denosumab , Fibrous Dysplasia of Bone , Animals , Humans , Mice , Denosumab/pharmacology , Fibrous Dysplasia of Bone/drug therapy , Ligands , Osteoblasts/metabolism , Osteogenesis/genetics
6.
Nature ; 623(7987): 616-624, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37938773

ABSTRACT

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.


Subject(s)
Arthritis, Rheumatoid , Humans , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Cytokines/metabolism , Inflammation/complications , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Synovial Membrane/pathology , T-Lymphocytes/immunology , B-Lymphocytes/immunology , Genetic Predisposition to Disease/genetics , Phenotype , Single-Cell Gene Expression Analysis
7.
Endocrinol Metab (Seoul) ; 38(5): 504-521, 2023 10.
Article in English | MEDLINE | ID: mdl-37749800

ABSTRACT

Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor ß (TGFß)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFß and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFß causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3ß/ß-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFß+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.


Subject(s)
NF-kappa B , Osteogenesis , Mice , Animals , NF-kappa B/metabolism , TNF Receptor-Associated Factor 3/metabolism , Ligands , Osteoclasts/metabolism , Osteoclasts/pathology , Transforming Growth Factor beta/metabolism
8.
Front Endocrinol (Lausanne) ; 14: 1090049, 2023.
Article in English | MEDLINE | ID: mdl-36875448

ABSTRACT

Cellular senescence plays important roles in age-related diseases, including musculoskeletal disorders. Senescent cells (SCs) exert a senescence-associated secretory phenotype (SASP) by producing SASP factors, some of which overlap with factors produced by inflammatory cells (Inf-Cs). However, the differences between SCs and Inf-Cs and how they interact with each other during fracture repair have not been well studied. Here, we analyzed single cell RNA sequencing data of aged mouse fracture callus stromal cells. We defined Inf-Cs as cells that express NF-κB Rela/Relb, SCs as cells that express the senescence genes, Cdkn1a, Cdkn2a or Cdkn2c, and inflammatory SCs (Inf-SCs) as cells that express both NF-κB and senescence genes. Differentially expressed genes and pathway analyses revealed that Inf-SCs and SCs had a similar gene expression profile and upregulated pathways that are related to DNA damage/oxidation-reduction and cellular senescence, while Inf-Cs expressed different gene signatures and pathways from SCs and Inf-SCs, mainly related to inflammation. Cellchat software analysis indicated that SCs and Inf-SCs are potential ligand-producing cells that affect Inf-Cs as target cells. Cell culture experiments demonstrated that SC conditioned medium promoted inflammatory gene expression by callus-derived mesenchymal progenitor cells, and Inf-Cs had reduced osteoblast differentiation capacity. In summary, we have identified three cell subclusters associated with inflammation and senescence in callus stromal cells, predicted potential effects of Inf-SCs and SCs on Inf-Cs by production of active ligands, and demonstrated that when mesenchymal progenitors acquire inflammatory phenotypes their osteogenic potential is reduced.


Subject(s)
Fractures, Bone , NF-kappa B , Animals , Mice , Stromal Cells , Osteogenesis , Cellular Senescence
10.
Nat Commun ; 14(1): 159, 2023 01 11.
Article in English | MEDLINE | ID: mdl-36631487

ABSTRACT

TGFß1 induces age-related bone loss by promoting degradation of TNF receptor-associated factor 3 (TRAF3), levels of which decrease in murine and human bone during aging. We report that a subset of neutrophils (TGFß1+CCR5+) is the major source of TGFß1 in murine bone. Their numbers are increased in bone marrow (BM) of aged wild-type mice and adult mice with TRAF3 conditionally deleted in mesenchymal progenitor cells (MPCs), associated with increased expression in BM of the chemokine, CCL5, suggesting that TRAF3 in MPCs limits TGFß1+CCR5+ neutrophil numbers in BM of young mice. During aging, TGFß1-induced TRAF3 degradation in MPCs promotes NF-κB-mediated expression of CCL5 by MPCs, associated with higher TGFß1+CCR5+ neutrophil numbers in BM where they induce bone loss. TGFß1+CCR5+ neutrophils decreased bone mass in male mice. The FDA-approved CCR5 antagonist, maraviroc, reduced TGFß1+CCR5+ neutrophil numbers in BM and increased bone mass in aged mice. 15-mon-old mice with TGFßRII specifically deleted in MPCs had lower numbers of TGFß1+CCR5+ neutrophils in BM and higher bone volume than wild-type littermates. We propose that pharmacologic reduction of TGFß1+CCR5+ neutrophil numbers in BM could treat or prevent age-related osteoporosis.


Subject(s)
Bone Marrow , Neutrophils , Osteoporosis , Animals , Male , Mice , Bone Marrow/metabolism , Bone Marrow/pathology , Maraviroc , Neutrophils/metabolism , Osteoporosis/metabolism , Osteoporosis/pathology , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , TNF Receptor-Associated Factor 3/metabolism , Transforming Growth Factor beta
11.
Article in English | MEDLINE | ID: mdl-36701241

ABSTRACT

Heterotopic ossification (HO) typically presents in the hip, knee, and elbow joints in the setting of trauma or postsurgical intervention. Less commonly, it may occur secondary to neurologic dysfunction or underlying genetic conditions, but idiopathic HO is rare. Most cases of HO are managed nonoperatively with surgical resection remaining a controversy due to high recurrence rates. We describe a case of idiopathic HO of the shoulder that occurred in the absence of trauma, neurologic dysfunction, or underlying genetic disorder that was treated with surgical excision.


Subject(s)
Elbow Joint , Nervous System Diseases , Ossification, Heterotopic , Humans , Pregnancy , Female , Neoplasm Recurrence, Local , Elbow Joint/surgery , Ossification, Heterotopic/diagnostic imaging , Ossification, Heterotopic/surgery , Knee Joint
12.
Nat Commun ; 13(1): 6107, 2022 10 16.
Article in English | MEDLINE | ID: mdl-36245043

ABSTRACT

Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of succinate dehydrogenase C (SDHC), a direct HSF1 target. Forced expression of SDHC largely restores the Hsf1 ablation-induced AML developmental defect. Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML.


Subject(s)
Cell Self Renewal , Leukemia, Myeloid, Acute , Humans , Cell Self Renewal/genetics , Heat Shock Transcription Factors/genetics , Heat Shock Transcription Factors/metabolism , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Neoplastic Stem Cells/metabolism , Succinate Dehydrogenase/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
14.
Int J Clin Exp Pathol ; 15(7): 282-288, 2022.
Article in English | MEDLINE | ID: mdl-35949810

ABSTRACT

BACKGROUND: The ligamentum teres (LT) is covered by synovium. It acts as a stabilizer of the hip and as such it has been compared to the ACL of the knee joint. Pathologic changes occur in the LT with aging and osteoarthritis (OA), including degeneration, occasional chondroid metaplasia, and synovial chondromatosis are well-recognized in the literature. However, there are no reports of intraligamentous synovial osteochondroma occuring in the LT. METHODS: We reviewed the pathology reports of 542 osteoarthritic femoral arthroplasty specimens between January 2016 and December 2018. The LT was examined histologically in 55 cases because it was abnormal on gross examination. RESULTS: A single synovial osteochondroma, ranging in size from 0.4-1.7 cm in diameter, was present in the body of the LT in 14 cases (9 males; 5 females, aged 34 to 81 years), representing 2.6% of 542 arthroplasty cases. Ten of the osteochondromas had bone marrow fat without hematopoietic elements, 1 had hematopoietic elements, and 3 had no marrow among the bony trabeculae. Radiographically, all cases had moderate to severe osteoarthritis with no mention of an abnormality of LT. CONCLUSION: To our knowledge, this is the first report of intraligamentous synovial osteochondroma in the LT in osteoarthritis patients undergoing hip arthroplasty. It provides further support for microscopic examination of arthroplasty specimens for histologic abnormalities. Further prospective study is needed to determine if this lesion contributes adversely to the development or progression of osteoarthritis and if it is a reactive or neoplastic process.

15.
Article in English | MEDLINE | ID: mdl-35797605

ABSTRACT

Complex regional pain syndrome (CRPS) is a potentially devastating condition that can result in severe psychological and social morbidity. It is a diagnosis of exclusion, and other pathologic entities must be ruled out first. Glomus tumors are exquisitely painful benign vascular tumors that are most common in the hand and are rarely found in the lower extremity. Here, we present a case of a patient who developed a focus of severe anterior knee pain and tenderness a few months after a car accident that had been misdiagnosed as CRPS for 15 years. She coincidentally developed a sarcoma of her ipsilateral leg distal to this site. Magnetic resonance imaging of the sarcoma included the area of knee pain where, interestingly, it identified a separate small soft-tissue mass. A glomus tumor was diagnosed histologically in a needle biopsy specimen from this mass, which was resected along with the sarcoma. For the first time in 15 years, despite the additional sarcoma surgery, she reported relief of her pain and complete resolution of her "CRPS."


Subject(s)
Complex Regional Pain Syndromes , Glomus Tumor , Histiocytoma, Malignant Fibrous , Soft Tissue Neoplasms , Complex Regional Pain Syndromes/diagnosis , Complex Regional Pain Syndromes/etiology , Diagnostic Errors , Female , Glomus Tumor/diagnosis , Glomus Tumor/surgery , Humans , Lower Extremity , Pain , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/diagnostic imaging
16.
Innovations (Phila) ; 17(3): 217-222, 2022.
Article in English | MEDLINE | ID: mdl-35578543

ABSTRACT

Objective: Surgical aortic valve replacement (SAVR) carries the known risk of shedding debris into the left ventricle during valve leaflet excision and annulus debridement. Embolization of this debris may have devastating effects for the patient. Although surgeons have developed methods to mitigate this risk, no data exist as to their efficacy. Herein, we present the first study that evaluates the efficacy of a technique for capturing debris during SAVR. Methods: Our group conducted a prospective case series of 20 patients who underwent SAVR using the insertion of an intraventricular surgical sponge prior to valve leaflet excision and annulus debridement to capture debris. Surgical sponges were grossly, radiographically, and histologically examined for the presence of cellular and acellular debris to determine the efficacy of this technique. Results: Of the 20 surgical sponges analyzed, 15 specimens (75%) registered positivity for cellular and/or acellular debris. Seven sponges (35%) were grossly positive, 15 sponges (75%) were radiographically positive, and 4 sponges (20%) were histologically positive for calcified debris on examination. Conclusions: This is one of the few studies to objectively evaluate a method used to capture debris in SAVR procedures. Our results demonstrate a high frequency of debris captured within intraventricular surgical sponges and confirms the efficacy of this technique. While these data are promising, numerous additional approaches exist to capture debris, and a best practice standard should exist across the specialty.  In addition, this study does not address the clinical outcomes associated with this technique. To these ends, additional data and multicenter collaboration are required.


Subject(s)
Aortic Valve Stenosis , Heart Valve Prosthesis Implantation , Heart Valve Prosthesis , Transcatheter Aortic Valve Replacement , Aortic Valve/surgery , Aortic Valve Stenosis/surgery , Heart Valve Prosthesis Implantation/methods , Humans , Risk Factors , Transcatheter Aortic Valve Replacement/methods , Treatment Outcome
17.
J Clin Invest ; 132(8)2022 04 15.
Article in English | MEDLINE | ID: mdl-35426372

ABSTRACT

Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated secretory phenotype to affect the function of neighboring cells and SCs themselves. Delayed fracture healing is common in the elderly and is accompanied by reduced mesenchymal progenitor cells (MPCs). However, the contribution of cellular senescence to fracture healing in the aged has not to our knowledge been studied. Here, we used C57BL/6J 4-month-old young and 20-month-old aged mice and demonstrated a rapid increase in SCs in the fracture callus of aged mice. The senolytic drugs dasatinib plus quercetin enhanced fracture healing in aged mice. Aged callus SCs inhibited the growth and proliferation of callus-derived MPCs (CaMPCs) and expressed high levels of TGF-ß1. TGF-ß-neutralizing Ab prevented the inhibitory effects of aged callus SCs on CaMPCs and promoted fracture healing in aged mice, which was associated with increased CaMPCs and proliferating cells. Thus, fracture triggered a significant cellular senescence in the callus cells of aged mice, which inhibited MPCs by expressing TGF-ß1. Short-term administration of dasatinib plus quercetin depleted callus SCs and accelerated fracture healing in aged mice. Senolytic drugs represent a promising therapy, while TGF-ß1 signaling is a molecular mechanism for fractures in the elderly via SCs.


Subject(s)
Fracture Healing , Fractures, Bone , Animals , Cellular Senescence , Dasatinib/pharmacology , Fractures, Bone/drug therapy , Fractures, Bone/genetics , Mice , Mice, Inbred C57BL , Quercetin/pharmacology , Transforming Growth Factor beta1/genetics
18.
Ann Rheum Dis ; 81(12): 1640-1646, 2022 12.
Article in English | MEDLINE | ID: mdl-35210263

ABSTRACT

BACKGROUND: Synovial tissue research has become widely developed in several rheumatology centres, however, large discrepancies exist in the way synovial tissue is handled and, more specifically, how data pertaining to biopsy procedure, quality check and experimental results are reported in the literature. This heterogeneity hampers the progress of research in this rapidly expanding field. In that context, under the umbrella of European Alliance of Associations for Rheumatology, we aimed at proposing points to consider (PtC) for minimal reporting requirements in synovial tissue research. METHODS: Twenty-five members from 10 countries across Europe and USA met virtually to define the key areas needing evaluation and formulating the research questions to inform a systematic literature review (SLR). The results were presented during a second virtual meeting where PtC were formulated and agreed. RESULTS: Study design, biopsy procedures, tissue handling, tissue quality control and tissue outcomes (imaging, DNA/RNA analysis and disaggregation) were identified as important aspects for the quality of synovial tissue research. The SLR interrogated four databases, retrieved 7654 abstracts and included 26 manuscripts. Three OPs and nine PtC were formulated covering the following areas: description of biopsy procedure, overarching clinical design, patient characteristics, tissue handling and processing, quality control, histopathology, transcriptomic analyses and single-cell technologies. CONCLUSIONS: These PtC provide guidance on how research involving synovial tissue should be reported to ensure a better evaluation of results by readers, reviewers and the broader scientific community. We anticipate that these PtC will enable the field to progress in a robust and transparent manner over the coming years.


Subject(s)
Rheumatology , Humans , Synovial Membrane/pathology , Biopsy/methods , Europe
19.
PLoS One ; 17(2): e0263839, 2022.
Article in English | MEDLINE | ID: mdl-35213543

ABSTRACT

The ubiquitin/proteasome system controls the stability of Runx2 and JunB, proteins essential for differentiation of mesenchymal progenitor/stem cells (MPCs) to osteoblasts. Local administration of proteasome inhibitor enhances bone fracture healing by accelerating endochondral ossification. However, if a short-term administration of proteasome inhibitor enhances fracture repair and potential mechanisms involved have yet to be exploited. We hypothesize that injury activates the ubiquitin/proteasome system in callus, leading to elevated protein ubiquitination and degradation, decreased MPCs, and impaired fracture healing, which can be prevented by a short-term of proteasome inhibition. We used a tibial fracture model in Nestin-GFP reporter mice, in which a subgroup of MPCs are labeled by Nestin-GFP, to test our hypothesis. We found increased expression of ubiquitin E3 ligases and ubiquitinated proteins in callus tissues at the early phase of fracture repair. Proteasome inhibitor Bortezomib, given soon after fracture, enhanced fracture repair, which is accompanied by increased callus Nestin-GFP+ cells and their proliferation, and the expression of osteoblast-associated genes and Runx2 and JunB proteins. Thus, early treatment of fractures with Bortezomib could enhance the fracture repair by increasing the number and proliferation of MPCs.


Subject(s)
Bortezomib/pharmacology , Cell Proliferation/drug effects , Fracture Healing/drug effects , Mesenchymal Stem Cells/enzymology , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/pharmacology , Tibial Fractures/enzymology , Animals , Cell Proliferation/genetics , Core Binding Factor Alpha 1 Subunit/biosynthesis , Core Binding Factor Alpha 1 Subunit/genetics , Disease Models, Animal , Fracture Healing/genetics , Male , Mice , Mice, Transgenic , Osteoblasts/enzymology , Proteasome Endopeptidase Complex/genetics , Tibial Fractures/drug therapy , Tibial Fractures/genetics , Transcription Factors/biosynthesis , Transcription Factors/genetics , Ubiquitin-Protein Ligases/biosynthesis , Ubiquitin-Protein Ligases/genetics
20.
J Bone Miner Res ; 37(4): 629-642, 2022 04.
Article in English | MEDLINE | ID: mdl-34970782

ABSTRACT

Limited treatment options exist for cancer within the bone, as demonstrated by the inevitable, pernicious course of metastatic and blood cancers. The difficulty of eliminating bone-residing cancer, especially drug-resistant cancer, necessitates novel, alternative treatments to manipulate tumor cells and their microenvironment, with minimal off-target effects. To this end, bone-targeted conjugate (BP-Btz) was generated by linking bortezomib (Btz, an anticancer, bone-stimulatory drug) to a bisphosphonate (BP, a targeting ligand) through a cleavable linker that enables spatiotemporally controlled delivery of Btz to bone under acidic conditions for treating multiple myeloma (MM). Three conjugates with different linkers were developed and screened for best efficacy in mouse model of MM. Results demonstrated that the lead candidate BP-Btz with optimal linker could overcome Btz resistance, reduced tumor burden, bone destruction, or tumor metastasis more effectively than BP or free Btz without thrombocytopenia and neurotoxicity in mice bearing myeloma. Furthermore, pharmacokinetic and pharmacodynamic studies showed that BP-Btz bound to bone matrix, released Btz in acidic conditions, and had a higher local concentration and longer half-life than Btz in bone. Our findings suggest the potential of bone-targeted Btz conjugate as an efficacious Btz-resistant MM treatment mechanism. © 2021 American Society for Bone and Mineral Research (ASBMR).


Subject(s)
Antineoplastic Agents , Bone Neoplasms , Multiple Myeloma , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Bone and Bones/pathology , Bortezomib/pharmacology , Bortezomib/therapeutic use , Cell Line, Tumor , Drug Resistance, Neoplasm , Mice , Multiple Myeloma/pathology , Tumor Microenvironment
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