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1.
Orthop Surg ; 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39117579

RESUMO

OBJECTIVE: Postmenopausal changes in bone mass and structure compromise the mechanical properties of proximal humerus, predisposing it to low-energy fractures with complex morphology. The aim of the study is to investigate associations of bone quality and estimated bone strength of the surgical neck with age after menopause. METHODS: A total of 122 healthy postmenopausal women were recruited from December 2016 to December 2022 and assigned to three groups: the 50-59 years group, the 60-69 years group, and the older than 70 years group. Bone properties of the surgical neck, including volumetric bone mineral density (vBMD), cortical thickness (CTh), the periosteal and medullary size, and estimated indices of bone strength were evaluated by quantitative computed tomography. RESULTS: Compared to the 50-59 years group, postmenopausal women aged over 70 years were characterized by lower cortical thickness (13.9%) and vBMD (6.65%), as well as reduced strength indices including the minimum and maximum section modulus (Zmin 18.11%, Zmax 21.71%), polar section modulus (Zpol 20.21%), and the minimum and maximum second moments of area (Imax 21.01%, Imin 21.43%). Meanwhile, the difference in periosteal diameter and perimeter, total area in three groups did not reach statistical significance. Both cortical thickness and vBMD value were inversely associated with age, showing 10.56% and 23.92% decline. Imax showed the greatest age-related decrease between age of 54 and 86 years (39.08%), followed by Zmax (-35.77%), Imin (-35.73%), Zpol (-34.90%) and Imin (-23.92%).The strength indices had stronger correlations with cortical thickness than with bone size or density. CONCLUSION: In postmenopausal women, aging is associated with a significant decline in cortical bone thickness and mechanical strength of the proximal humerus, especially over the age of 70 years.

2.
J Bone Miner Res ; 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39052334

RESUMO

Only in the past decade have skeletal stem cells (SSCs), a cell type displaying formal evidence of stemness and serving as the ultimate origin of mature skeletal cell types such as osteoblasts, been defined. Here, we discuss a pair of recent reports that identify that SSCs do not represent a single cell type, but rather a family of related cells that each have characteristic anatomic locations and distinct functions tailored to the physiology of those sites. The distinct functional properties of these SSCs in turn provide a basis for the diseases of their respective locations. This concept emerges from one report identifying a distinct vertebral skeletal stem cell driving the high rate of breast cancer metastasis to the spine over other skeletal sites and a report identifying two SSCs in the calvaria that interact to mediate both physiologic calvarial mineralization and pathologic calvarial suture fusion in craniosynostosis. Despite displaying functional differences, these SSCs are each united by shared features including a shared series of surface markers and parallel differentiation hierarchies. We propose that this diversity at the level of SSCs in turn translates into a similar diversity at the level of mature skeletal cell types, including osteoblasts, with osteoblasts derived from different SSCs each displaying different functional and transcriptional characteristics reflecting their cell of origin. In this model, osteoblasts would represent not a single cell type, but rather a family of related cells each with distinct functions, paralleling the functional diversity in SSCs.


Only in the past decade have the stem cells in the skeleton been identified. Here, we discuss a pair of recent reports that identify that skeletal stem cells are actually a family of related cells that each have distinct locations and functions. These site-specific skeletal stem cells account for the signature diseases occurring in different regions of the skeleton. Specifically, one of these stem cells forms the spine and establishes that this stem cell drives the high rate of breast cancer metastasis to the spine over other skeletal sites. There are also at least two skeletal stem cells in the flat bones of the skull, with mutations alerting how these two stem cells "talk" to each other serving as a cause for disorders of premature skull fusion. Despite displaying differences in their function, these stem cells are each united by shared features including a partially shared series marker genes. We also here propose that this diversity at the level of skeletal stem cells translates into a similar diversity in mature skeletal cell types, including osteoblasts. In this model, osteoblasts are not a single cell type, but rather a family of related cells each with distinct functions.

3.
JBMR Plus ; 8(7): ziae070, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38868596

RESUMO

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.
J Bone Miner Res ; 39(6): 729-736, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-38640512

RESUMO

Romosozumab treatment results in a transient early increase in bone formation and sustained decrease in bone resorption. Histomorphometric analyses revealed that the primary bone-forming effect of romosozumab is a transient early stimulation of modeling-based bone formation on cancellous and endocortical surfaces. Furthermore, preclinical studies have demonstrated that romosozumab may affect changes in the remodeling unit, resulting in positive bone balance. To further investigate the effects of romosozumab on bone balance, mo 12 (M12) and mo 2 (M2) (to analyze early effects) unpaired bone biopsies from the FRAME clinical trial were analyzed using remodeling site reconstruction to assess whether positive changes in bone balance on cancellous/endocortical surfaces may contribute to the progressive improvement in bone mass/structure and reduced fracture risk in osteoporotic women at high fracture risk. At M12, bone balance was higher with romosozumab vs placebo on cancellous (+6.1 vs +1.5 µm; P = .012) and endocortical (+5.2 vs -1.7 µm; P = .02) surfaces; higher bone balance was due to lower final erosion depth (40.7 vs 43.7 µm; P = .05) on cancellous surfaces and higher completed wall thickness (50.8 vs 47.5 µm; P = .037) on endocortical surfaces. At M2, the final erosion depth was lower on the endocortical surfaces (42.7 vs 50.7 µm; P = .021) and was slightly lower on the cancellous surfaces (38.5 vs 44.6 µm; P = .11) with romosozumab vs placebo. Sector analysis of early endocortical formative sites revealed higher osteoid thickness (29.9 vs 19.2 µm; P = .005) and mineralized wall thickness (18.3 vs 11.9 µm; P = .004) with romosozumab vs placebo. These evolving bone packets may reflect the early stimulation of bone formation that contributes to the increase in completed wall thickness at M12. These data suggest that romosozumab induces a positive bone balance due to its effects on bone resorption and formation at the level of the remodeling unit, contributing to the positive effects on bone mass, structure, and fracture risk.


Romosozumab treatment has a dual effect on bone, adding new bone and reducing bone loss. In the FRAME clinical trial, romosozumab increased the bone mass and strength and reduced fracture risk in postmenopausal women with osteoporosis. Addition of new bone occurs early in treatment and rapidly on cancellous and endocortical bone surfaces where bone resorption is not ongoing. However, it remains unclear if romosozumab affects bone loss or gain in areas where bone resorption is ongoing (remodeling units), contributing to a further positive bone balance. Here, we examined whether changes at the remodeling unit occur early (2 mo) and/or late (12 mo) in treatment by using bone biopsies from patients treated with romosozumab or placebo in FRAME. At M2, a combination of lower bone resorption and higher bone gain on endocortical surfaces resulted in a positive bone balance with romosozumab vs placebo. At M12, the bone balance was positive with romosozumab vs placebo due to lower bone resorption on cancellous surfaces and greater bone gain on endocortical surfaces. This demonstrates that romosozumab induces a positive bone balance at remodeling units early in treatment, leading to overall gains observed later, contributing to the positive effects of romosozumab on bone mass and structure.


Assuntos
Anticorpos Monoclonais , Remodelação Óssea , Humanos , Feminino , Remodelação Óssea/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Idoso , Densidade Óssea/efeitos dos fármacos , Pessoa de Meia-Idade
5.
J Bone Miner Res ; 39(3): 357-372, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38477738

RESUMO

Sphingosine-1-phosphate (S1P) plays multiple roles in bone metabolism and regeneration. Here, we have identified a novel S1P-regulated osteoanabolic mechanism functionally connecting osteoblasts (OBs) to the highly specialized bone vasculature. We demonstrate that S1P/S1PR3 signaling in OBs stimulates vascular endothelial growth factor a (VEGFa) expression and secretion to promote bone growth in an autocrine and boost osteogenic H-type differentiation of bone marrow endothelial cells in a paracrine manner. VEGFa-neutralizing antibodies and VEGF receptor inhibition by axitinib abrogated OB growth in vitro and bone formation in male C57BL/6J in vivo following S1P stimulation and S1P lyase inhibition, respectively. Pharmacological S1PR3 inhibition and genetic S1PR3 deficiency suppressed VEGFa production, OB growth in vitro, and inhibited H-type angiogenesis and bone growth in male mice in vivo. Together with previous work on the osteoanabolic functions of S1PR2 and S1PR3, our data suggest that S1P-dependent bone regeneration employs several nonredundant positive feedback loops between OBs and the bone vasculature. The identification of this yet unappreciated aspect of osteoanabolic S1P signaling may have implications for regular bone homeostasis as well as diseases where the bone microvasculature is affected such as age-related osteopenia and posttraumatic bone regeneration.


Sphingosine-1-phosphate (S1P) is a signaling lipid that regulates bone growth and regeneration. In the present study, a novel regenerative mechanism was connected to S1P signaling within the bone. Activation of its receptor S1PR3 in bone-forming osteoblasts led to secretion of vascular endothelial growth factor a (VEGFa), the most potent vessel-stimulating factor. This stimulated the development of specialized vessels of the bone marrow, the H-type vessels, that supported overall bone regeneration. These findings foster our understanding of regular bone metabolism and suggest that S1P-based drugs may help treat diseases such as age-related osteopenia and posttraumatic bone regeneration, conditions crucially dependent on functional bone microvasculature.


Assuntos
Lisofosfolipídeos , Receptores de Lisoesfingolipídeo , Esfingosina/análogos & derivados , Fator A de Crescimento do Endotélio Vascular , Masculino , Camundongos , Animais , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Esfingosina-1-Fosfato , Fator A de Crescimento do Endotélio Vascular/metabolismo , Osteogênese , Células Endoteliais/metabolismo , Camundongos Endogâmicos C57BL , Osteoblastos/metabolismo
6.
J Bone Miner Res ; 39(3): 202-210, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38477751

RESUMO

Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration-time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect-time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis.


Denosumab is a biologic treatment that stops bone breakdown. This clinical trial evaluated how similar GP2411 (a denosumab biosimilar in development) is compared with European-approved reference denosumab in women with post-menopausal osteoporosis. Biosimilars are highly similar to the original treatment ('reference denosumab') and may have a lower price. 263 patients were randomly assigned to receive GP2411 and 264 to reference denosumab. Treatment was given at the study beginning, at Week 26 and at Week 52. 124 patients were re-assigned at Week 52 to test the effect of changing from reference denosumab to GP2411. The study showed similarity in how the body interacts with the treatments, what effects the treatment has (both measured over 26 weeks), and bone mineral density (measured over 78 weeks). Antibody responses to GP2411 were detected in similar proportions of patients on each treatment. Reported adverse events were similar between treatments before Week 52, and from Week 52 to 78, and <5% of patients experienced serious adverse events. A change of treatment from reference denosumab to GP2411 did not affect outcomes. These results showed similarity between GP2411 and reference denosumab in this population. In future, GP2411 may enable more patients to benefit from denosumab.


Assuntos
Medicamentos Biossimilares , Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Feminino , Humanos , Medicamentos Biossimilares/efeitos adversos , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/efeitos adversos , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Método Duplo-Cego
7.
J Bone Miner Res ; 39(3): 195-196, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38493502
8.
JBMR Plus ; 8(4): ziae017, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38523666

RESUMO

Children with hemato-oncological diseases may have significant skeletal morbidity, not only during and after treatment but also at the time of diagnosis before cancer treatment. This study was designed to evaluate the vitamin D status and circulating bone metabolic markers and their determinants in children at the time of diagnostic evaluation for hemato-oncological disease. This cross-sectional study included 165 children (91 males, median age 6.9 yr range 0.2-17.7 yr). Of them, 76 patients were diagnosed with extracranial or intracranial solid tumors, 83 with leukemia, and 6 with bone marrow failure. Bone metabolism was assessed by measuring serum 25OHD, PTH, bone alkaline phosphatase, intact N-terminal propeptide of type I procollagen, and C-terminal cross-linked telopeptide of type I collagen. Vitamin D deficiency was found in 30.9% of children. Lower 25OHD levels were associated with older age, lack of vitamin D supplementation, season outside summer, and a country of parental origin located between latitudes -45° and 45°. Children diagnosed with leukemia had lower levels of markers of bone formation and bone resorption than those who had solid tumors or bone marrow failure. In conclusion, vitamin D deficiency was observed in one-third of children with newly diagnosed cancer. Bone turnover markers were decreased in children with leukemia, possibly because of the suppression of osteoblasts and osteoclasts by leukemic cells. The identification of patients with suboptimal vitamin D status and compromised bone remodeling at cancer diagnosis may aid in the development of supportive treatment to reduce the adverse effects of cancer and its treatment.

9.
JBMR Plus ; 7(12): e10806, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38130760

RESUMO

Prior work demonstrated that Phlpp1 deficiency alters limb length and bone mass, but the cell types involved and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within bone-forming osteoblasts, we crossed Phlpp1 floxed mice with mice harboring type 1 collagen (Col1a12.3kb)-Cre. Mineralization of bone marrow stromal cell cultures derived from Phlpp1 cKOCol1a1 was unchanged, but levels of inflammatory genes (eg, Ifng, Il6, Ccl8) and receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratios were enhanced by either Phlpp1 ablation or chemical inhibition. Micro-computed tomography of the distal femur and L5 vertebral body of 12-week-old mice revealed no alteration in bone volume per total volume, but compromised femoral bone microarchitecture within Phlpp1 cKOCol1a1 conditional knockout females. Bone histomorphometry of the proximal tibia documented no changes in osteoblast or osteoclast number per bone surface but slight reductions in osteoclast surface per bone surface. Overall, our data show that deletion of Phlpp1 in type 1 collagen-expressing cells does not significantly alter attainment of peak bone mass of either males or females, but may enhance inflammatory gene expression and the ratio of RANKL/OPG. Future studies examining the role of Phlpp1 within models of advanced age, inflammation, or osteocytes, as well as functional redundancy with the related Phlpp2 isoform are warranted. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

10.
JBMR Plus ; 7(10): e10802, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37808400

RESUMO

Activating parathyroid hormone (PTH)/PTH-related Peptide (PTHrP) receptor (PTH1R) mutations causes Jansen's metaphyseal chondrodysplasia (JMC), a rare disease characterized by growth plate abnormalities, short stature, and PTH-independent hypercalcemia. Previously generated transgenic JMC mouse models, in which the human PTH1R allele with the H223R mutation (H223R-PTH1R) is expressed in osteoblasts via type Ia1 collagen or DMP1 promoters cause excess bone mass, while expression of the mutant allele via the type IIa1 collagen promoter results in only minor growth plate changes. Thus, neither transgenic JMC model adequately recapitulates the human disease. We therefore generated "humanized" JMC mice in which the H223R-PTH1R allele was expressed via the endogenous mouse Pth1r promoter and, thus, in all relevant target tissues. Founders with the H223R allele typically died within 2 months without reproducing; several mosaic male founders, however, lived longer and produced F1 H223R-PTH1R offspring, which were small and exhibited marked growth plate abnormalities. Serum calcium and phosphate levels of the mutant mice were not different from wild-type littermates, but serum PTH and P1NP were reduced significantly, while CTX-1 and CTX-2 were slightly increased. Histological and RNAscope analyses of the mutant tibial growth plates revealed markedly expanded zones of type II collagen-positive, proliferating/prehypertrophic chondrocytes, abundant apoptotic cells in the growth plate center and a progressive reduction of type X collagen-positive hypertrophic chondrocytes and primary spongiosa. The "humanized" H223R-PTH1R mice are likely to provide a more suitable model for defining the JMC phenotype and for assessing potential treatment options for this debilitating disease of skeletal development and mineral ion homeostasis. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

11.
JBMR Plus ; 7(8): e10785, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37614299

RESUMO

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect of antiresorptive medications administered for control of osseous malignancy, osteoporosis, or other bone metabolic diseases. Despite being reported in the literature two decades ago, MRONJ etiology, pathophysiology, and progression remain largely unknown, and current nonoperative or operative treatment strategies are mostly empirical. Several hypotheses that attempt to explain the mechanisms of MRONJ pathogenesis have been proposed. However, none of these hypotheses alone is able to capture the complex mechanistic underpinnings of the disease. In this minireview, we aim to highlight key findings from clinical and translational studies and propose a unifying model for the pathogenesis and progression of MRONJ. We also identify aspects of the disease process that require further investigation and suggest areas for future research efforts toward calibrating methodologic approaches and validating experimental findings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

12.
J Bone Miner Res ; 38(10): 1480-1496, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37537994

RESUMO

Adipose-derived stromal/stem cells (ASCs) have been extensively studied as cell sources for regenerative medicine for bone because of their excellent proliferative capacity and the ability to obtain a large number of cells with minimal donor morbidity. On the other hand, the differentiation potential of ASCs is generally lower than that of bone marrow-derived stromal/stem cells and varies greatly depending on donors. In this study, we mined a marker that can predict the osteogenic potential of ASC clones and also investigated the usefulness of the molecule as the enhancer of osteogenic differentiation of ASCs as well as its mechanism of action. Through RNA-seq gene analysis, we discovered that GSTT1 (Glutathione S-transferase theta-1) was the most distinguished gene marker between highly osteogenic and poorly osteogenic ASC clones. Knockdown of GSTT1 in high osteogenic ASCs by siGSTT1 treatment reduced mineralized matrix formation. On the other hand, GSTT1 overexpression by GSTT1 transfection or GSTT1 recombinant protein treatment enhanced osteogenic differentiation of low osteogenic ASCs. Metabolomic analysis confirmed significant changes of metabolites related to bone differentiation in ASCs transfected with GSTT1. A high total antioxidant capacity, low levels of cellular reactive oxygen species, and increased GSH/GSSG ratios were also detected in GSTT1-transfected ASCs. When the in vivo effect of GSTT1-transfected ASCs on bone regeneration was investigated with segmental long-bone defect model in rats, bone regeneration was significantly better after implantation of GSTT1-transfected ASCs compared with that of control vector-transfected ASCs. In conclusion, GSTT1 can be a useful marker to screen the highly osteogenic ASC clones and also a therapeutic factor to enhance the osteogenic differentiation of poorly osteogenic ASC clones. © 2023 American Society for Bone and Mineral Research (ASBMR).

13.
J Bone Miner Res ; 38(9): 1364-1385, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37329499

RESUMO

Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic condition characterized by altered skeletal development and extraskeletal bone formation. All cases of FOP are caused by mutations in the type I bone morphogenetic protein (BMP) receptor gene ACVR1 that result in overactivation of the BMP signaling pathway. Activation of the wild-type ACVR1 kinase requires assembly of a tetrameric type I and II BMP receptor complex followed by phosphorylation of the ACVR1 GS domain by type II BMP receptors. Previous studies showed that the FOP-mutant ACVR1-R206H required type II BMP receptors and presumptive glycine/serine-rich (GS) domain phosphorylation for overactive signaling. Structural modeling of the ACVR1-R206H mutant kinase domain supports the idea that FOP mutations alter the conformation of the GS domain, but it is unclear how this leads to overactive signaling. Here we show, using a developing zebrafish embryo BMP signaling assay, that the FOP-mutant receptors ACVR1-R206H and -G328R have reduced requirements for GS domain phosphorylatable sites to signal compared to wild-type ACVR1. Further, ligand-independent and ligand-dependent signaling through the FOP-mutant ACVR1 receptors have distinct GS domain phosphorylatable site requirements. ACVR1-G328R showed increased GS domain serine/threonine requirements for ligand-independent signaling compared to ACVR1-R206H, whereas it exhibited reduced serine/threonine requirements for ligand-dependent signaling. Remarkably, while ACVR1-R206H does not require the type I BMP receptor partner, Bmpr1, to signal, a ligand-dependent GS domain mutant of ACVR1-R206H could signal independently of Bmpr1 only when Bmp7 ligand was overexpressed. Of note, unlike human ACVR1-R206H, the zebrafish paralog Acvr1l-R203H does not show increased signaling activity. However, in domain-swapping studies, the human kinase domain, but not the human GS domain, was sufficient to confer overactive signaling to the Acvr1l-R203H receptor. Together these results reflect the importance of GS domain activation and kinase domain functions in regulating ACVR1 signaling and identify mechanisms of reduced regulatory constraints conferred by FOP mutations. © 2023 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Miosite Ossificante , Animais , Humanos , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas/genética , Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Ligantes , Mutação/genética , Miosite Ossificante/genética , Miosite Ossificante/metabolismo , Transdução de Sinais/genética , Peixe-Zebra/metabolismo
14.
J Bone Miner Res ; 38(8): 1192-1207, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37191192

RESUMO

Chronic kidney disease (CKD) is characterized by kidney damage and loss of renal function. CKD mineral and bone disorder (CKD-MBD) describes the dysregulation of mineral homeostasis, including hyperphosphatemia and elevated parathyroid hormone (PTH) secretion, skeletal abnormalities, and vascular calcification. CKD-MBD impacts the oral cavity, with effects including salivary gland dysfunction, enamel hypoplasia and damage, increased dentin formation, decreased pulp volume, pulp calcifications, and altered jaw bones, contributing to clinical manifestations of periodontal disease and tooth loss. Underlying mechanisms are not fully understood, and CKD mouse models commonly require invasive procedures with high rates of infection and mortality. We aimed to characterize the dentoalveolar effects of an adenine diet (AD)-induced CKD (AD-CKD) mouse model. Eight-week-old C57BL/6J mice were provided either a normal phosphorus diet control (CTR) or adenine and high-phosphorus diet CKD to induce kidney failure. Mice were euthanized at 15 weeks old, and mandibles were collected for micro-computed tomography and histology. CKD mice exhibited kidney failure, hyperphosphatemia, and hyperparathyroidism in association with porous cortical bone in femurs. CKD mice showed a 30% decrease in molar enamel volume compared to CTR mice. Enamel wear was associated with reduced ductal components, ectopic calcifications, and altered osteopontin (OPN) deposition in submandibular salivary glands of CKD mice. Molar cusps in CKD mice were flattened, exposing dentin. Molar dentin/cementum volume increased 7% in CKD mice and pulp volume decreased. Histology revealed excessive reactionary dentin and altered pulp-dentin extracellular matrix proteins, including increased OPN. Mandibular bone volume fraction decreased 12% and bone mineral density decreased 9% in CKD versus CTR mice. Alveolar bone in CKD mice exhibited increased tissue-nonspecific alkaline phosphatase localization, OPN deposition, and greater osteoclast numbers. AD-CKD recapitulated key aspects reported in CKD patients and revealed new insights into CKD-associated oral defects. This model has potential for studying mechanisms of dentoalveolar defects or therapeutic interventions. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Hiperfosfatemia , Insuficiência Renal Crônica , Camundongos , Animais , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Adenina , Microtomografia por Raio-X , Hiperfosfatemia/complicações , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica/complicações , Fósforo
15.
J Bone Miner Res ; 38(5): 792-807, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36824055

RESUMO

Lipids play a crucial role in signaling and metabolism, regulating the development and maintenance of the skeleton. Membrane lipids have been hypothesized to act as intermediates upstream of orphan phosphatase 1 (PHOSPHO1), a major contributor to phosphate generation required for bone mineralization. Here, we spatially resolve the lipid atlas of the healthy mouse knee and demonstrate the effects of PHOSPHO1 ablation on the growth plate lipidome. Lipids spanning 17 subclasses were mapped across the knee joints of healthy juvenile and adult mice using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS), with annotation supported by shotgun lipidomics. Multivariate analysis identified 96 and 80 lipid ions with differential abundances across joint tissues in juvenile and adult mice, respectively. In both ages, marrow was enriched in phospholipid platelet activating factors (PAFs) and related metabolites, cortical bone had a low lipid content, whereas lysophospholipids were strikingly enriched in the growth plate, an active site of mineralization and PHOSPHO1 activity. Spatially-resolved profiling of PHOSPHO1-knockout (KO) mice across the resting, proliferating, and hypertrophic growth plate zones revealed 272, 306, and 296 significantly upregulated, and 155, 220, and 190 significantly downregulated features, respectively, relative to wild-type (WT) controls. Of note, phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, lysophosphatidylethanolamine, and phosphatidylethanolamine derived lipid ions were upregulated in PHOSPHO1-KO versus WT. Our imaging pipeline has established a spatially-resolved lipid signature of joint tissues and has demonstrated that PHOSPHO1 ablation significantly alters the growth plate lipidome, highlighting an essential role of the PHOSPHO1-mediated membrane phospholipid metabolism in lipid and bone homeostasis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Lipidômica , Monoéster Fosfórico Hidrolases , Camundongos , Animais , Monoéster Fosfórico Hidrolases/metabolismo , Lâmina de Crescimento/metabolismo , Camundongos Knockout , Homeostase , Fosfolipídeos
16.
JBMR Plus ; 7(1): e10703, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36699637

RESUMO

People living with HIV (PLWH) represent a vulnerable population to adverse musculoskeletal outcomes due to HIV infection, antiretroviral therapy (ART), and at-risk alcohol use. Developing measures to prevent skeletal degeneration in this group requires a grasp of the relationship between alcohol use and low bone mass in both the PLWH population and its constituents as defined by sex, age, and race. We examined the association of alcohol use with serum biochemical markers of bone health in a diverse cohort of PLWH enrolled in the New Orleans Alcohol Use in HIV (NOAH) study. To explore the effects of alcohol on bone in the context of HIV and ART and the role of estrogen, we conducted a parallel, translational study using simian immunodeficiency virus (SIV)+/ART+ female rhesus macaques divided into four groups: vehicle (Veh)/Sham; chronic binge alcohol (CBA)/Sham; Veh/ovariectomy (OVX); and CBA/OVX. Clinical data showed that both osteocalcin (Ocn) and procollagen type I N-propeptide (PINP) levels were inversely associated with multiple measures of alcohol consumption. Age (>50 years) significantly increased susceptibility to alcohol-associated suppression of bone formation in both female and male PLWH, with postmenopausal status appearing as an additional risk factor in females. Serum sclerostin (Scl) levels correlated positively with measures of alcohol use and negatively with Ocn. Micro-CT analysis of the macaque tibias revealed that although both CBA and OVX independently decreased trabecular number and bone mineral density, only OVX decreased trabecular bone volume fraction and impacted cortical geometry. The clinical data implicate circulating Scl in the pathogenesis of alcohol-induced osteopenia and suggest that bone morphology can be significantly altered in the absence of net change in osteoblast function as measured by serum markers. Inclusion of sophisticated tools to evaluate skeletal strength in clinical populations will be essential to understand the impact of alcohol-induced changes in bone microarchitecture. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

17.
J Bone Miner Res ; 38(2): 288-299, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36459048

RESUMO

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome caused by heterozygous NF1 gene mutations. Patients with NF1 present with pleiotropic somatic secondary manifestations, including development of bone pseudarthrosis after fracture. Somatic NF1 gene mutations were reproducibly identified in patient-derived pseudarthrosis specimens, suggesting a local mosaic cell population including somatic pathologic cells. The somatic cellular pathogenesis of NF1 pseudarthroses remains unclear, though defects in osteogenesis have been posited. Here, we applied time-series single-cell RNA-sequencing (scRNA-seq) to patient-matched control and pseudarthrosis-derived primary bone stromal cells (BSCs). We show that osteogenic specification to an osteoblast progenitor cell population was evident for control bone-derived cells and haploinsufficient pseudarthrosis-derived cells. Similar results were observed for somatic patient fracture-derived NF1-/- cells; however, expression of genetic pathways associated with skeletal mineralization were significantly reduced in NF1-/- cells compared with fracture-derived NF1+/- cells. In mice, we show that Nf1 expressed in bone marrow osteoprogenitors is required for the maintenance of the adult skeleton. Results from our study implicate impaired Clec11a-Itga11-Wnt signaling in the pathogenesis of NF1-associated skeletal disease. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Fraturas Ósseas , Neurofibromatose 1 , Pseudoartrose , Camundongos , Animais , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Pseudoartrose/genética , Pseudoartrose/metabolismo , Pseudoartrose/patologia , Fraturas Ósseas/patologia , Osteoblastos/metabolismo , Osteogênese/genética
18.
J Bone Miner Res ; 38(1): 48-58, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36270918

RESUMO

Musculoskeletal aging in the most resource-limited countries has not been quantified, and longitudinal data are urgently needed to inform policy. The aim of this prospective study was to describe musculoskeletal aging in Gambian adults. A total of 488 participants were recruited stratified by sex and 5-year age band (aged 40 years and older); 386 attended follow-up 1.7 years later. Outcomes were dual-energy X-ray absorptiometry (DXA) (n = 383) total hip areal bone mineral density (aBMD), bone mineral content (BMC), bone area (BA); peripheral quantitative computed tomography (pQCT) diaphyseal and epiphyseal radius and tibia (n = 313) total volumetric BMD (vBMD), trabecular vBMD, estimated bone strength indices (BSIc), cross-sectional area (CSA), BMC, and cortical vBMD. Mean annualized percentage change in bone outcomes was assessed in 10-year age bands and linear trends for age assessed. Bone turnover markers, parathyroid hormone (PTH), and 25-hydroxyvitamin D (25(OH)D) were explored as predictors of change in bone. Bone loss was observed at all sites, with an annual loss of total hip aBMD of 1.2% in women after age 50 years and in men at age 70 years plus. Greater loss in vBMD and BSIc was found at the radius in both men and women; strength was reduced by 4% per year in women and 3% per year in men (p trend 0.02, 0.03, respectively). At cortical sites, reductions in BMC, CSA, and vBMD were observed, being greatest in BMC in women, between 1.4% and 2.0% per annum. Higher CTX and PINP predicted greater loss of trabecular vBMD in women and BMC in men at the radius, and higher 25(OH)D with less loss of tibial trabecular vBMD and CSA in women. The magnitude of bone loss was like those reported in countries where fragility fracture rates are much higher. Given the predicted rise in fracture rates in resource-poor countries such as The Gambia, these data provide important insights into musculoskeletal health in this population. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Doenças Ósseas Metabólicas , Fraturas Ósseas , Masculino , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Densidade Óssea/fisiologia , Gâmbia/epidemiologia , Estudos Prospectivos , Absorciometria de Fóton , Envelhecimento/fisiologia , Fraturas Ósseas/epidemiologia , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/fisiologia , Músculos
19.
JBMR Plus ; 6(11): e10689, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36398107

RESUMO

Bone nodule formation by differentiating osteoblasts is considered an in vitro model that mimics bone modeling. However, the details of osteoblast behavior and matrix production during bone nodule formation are poorly understood. Here, we present a spatiotemporal analysis system for evaluating osteoblast morphology and matrix production during bone modeling in vitro via two-photon microscopy. Using this system, a change in osteoblast morphology from cuboidal to flat was observed during the formation of mineralized nodules, and this change was quantified. Areas with high bone formation were densely populated with cuboidal osteoblasts, which were characterized by blebs, protruding structures on their cell membranes. Cuboidal osteoblasts with blebs were highly mobile, and osteoblast blebs exhibited a polar distribution. Furthermore, mimicking romosozumab treatment, when differentiated flattened osteoblasts were stimulated with BIO, a GSK3ß inhibitor, they were reactivated to acquire a cuboidal morphology with blebs on their membranes and produced more matrix than nonstimulated cells. Our analysis system is a powerful tool for evaluating the cell morphology and function of osteoblasts during bone modeling. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

20.
Calcif Tissue Int ; 111(6): 547-558, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35978052

RESUMO

Osteoid is a layer of new-formed bone that is deposited on the bone border during the process of new bone formation. This deposition process is crucial for bone tissue, and flaws in it can lead to bone diseases. Certain bone diseases, i.e. medication related osteonecrosis, are overexpressed in mandibular bone. Because mandibular bone presents different properties than other bone types, the data concerning osteoid formation in other bones are inapplicable for human-mandibular bone. Previously, the molecular distribution of other bone types has been presented using Fourier-transform infrared (FTIR) spectroscopy. However, the spatial distribution of molecular components of healthy-human-mandibular-bone osteoid in relation to histologic landmarks has not been previously presented and needs to be studied in order to understand diseases that occur human-mandibular bone. This study presents for the first time the variation in molecular distribution inside healthy-human-mandibular-bone osteoid by juxtaposing FTIR data with its corresponding histologic image obtained by autofluorescence imaging of its same bone section. During new bone formation, bone-forming cells produce an osteoid constituted primarily of type I collagen. It was observed that in mandibular bone, the collagen type I increases from the osteoblast line with the distance from the osteoblasts, indicating progressive accumulation of collagen during osteoid formation. Only later inside the collagen matrix, the osteoid starts to mineralize. When the mineralization starts, the collagen accumulation diminishes whereas the collagen maturation still continues. This chemical-apposition process in healthy mandibular bone will be used in future as a reference to understand different pathologic conditions that occur in human-mandibular bone.


Assuntos
Doenças Ósseas , Osso e Ossos , Humanos , Matriz Óssea , Osteoblastos , Colágeno , Calcificação Fisiológica
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