-
European Journal of Endocrinology Jun 2024Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide...
Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide (ABL) increase bone formation, bone mineral density (BMD), and bone strength by activating PTH receptors on osteoblasts. Romosozumab (ROMO), a humanized monoclonal antibody against sclerostin, dramatically but transiently stimulates bone formation and persistently reduces bone resorption. Osteoanabolic agents increase BMD and bone strength while being more effective than antiresorptives in reducing fracture risk in postmenopausal women. However, direct comparisons of the antifracture benefits of osteoanabolic therapies are limited. In a direct comparison of TPTD and ABL, the latter resulted in greater BMD increases at the hip. While no differences in vertebral or non-vertebral fracture risk were observed between the two drugs, ABL led to a greater reduction of major osteoporotic fractures. Adverse event profiles were similar between the two agents except for hypercalcemia, which occurred more often with TPTD. No direct comparisons of fracture risk reduction between ROMO and the PTH1R agonists exist. Individual studies have shown greater increases in BMD and bone strength with ROMO compared to TPTD in treatment-naïve women and in women previously treated with bisphosphonates. Some safety aspects, such as a history of tumor precluding the use of PTH1R agonists, and a history of major cardiovascular events precluding the use of ROMO, should also be considered when choosing between these agents. Lastly, convenience of administration, reimbursement by national health systems and length of clinical experience may influence patient choice.
PubMed: 38938063
DOI: 10.1093/ejendo/lvae076 -
Cell Biology International Jun 2024Type 2 diabetic osteoporosis (T2DOP) is a skeletal metabolic syndrome characterized by impaired bone remodeling due to type 2 diabetes mellitus, and there are drawbacks...
Type 2 diabetic osteoporosis (T2DOP) is a skeletal metabolic syndrome characterized by impaired bone remodeling due to type 2 diabetes mellitus, and there are drawbacks in the present treatment. Osteoking (OK) is widely used for treating fractures and femoral head necrosis. However, OK is seldom reported in the field of T2DOP, and its role and mechanism of action need to be elucidated. Consequently, this study investigated whether OK improves bone remodeling and the mechanisms of diabetes-induced injury. We used db/db mice as a T2DOP model and stimulated MC3T3-E1 cells (osteoblast cell line) with high glucose (HG, 50 mM) and advanced glycation end products (AGEs, 100 µg/mL), respectively. The effect of OK on T2DOP was assessed using a combined 3-point mechanical bending test, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay. The effect of OK on enhancing MC3T3-E1 cell differentiation and mineralization under HG and AGEs conditions was assessed by an alkaline phosphatase activity assay and alizarin red S staining. The AGEs/insulin-like growth factor-1(IGF-1)/β-catenin/osteoprotegerin (OPG) pathway-associated protein levels were assayed by western blot analysis and immunohistochemical staining. We found that OK reduced hyperglycemia, attenuated bone damage, repaired bone remodeling, increased tibial and femoral IGF-1, β-catenin, and OPG expression, and decreased receptor activator of nuclear kappa B ligand and receptor activator of nuclear kappa B expression in db/db mice. Moreover, OK promoted the differentiation and mineralization of MC3T3-E1 cells under HG and AGEs conditions, respectively, and regulated the levels of AGEs/IGF-1/β-catenin/OPG pathway-associated proteins. In conclusion, our results suggest that OK may lower blood glucose, alleviate bone damage, and attenuate T2DOP, in part through activation of the AGEs/IGF-1/β-catenin/OPG pathway.
PubMed: 38937979
DOI: 10.1002/cbin.12215 -
Molecular Therapy : the Journal of the... Jun 2024Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately,...
Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3). SHN3 is a promising therapeutic target for alveolar bone regeneration, because SHN3 expression is elevated in human and mouse mandible tissues with osteoporosis while deletion of SHN3 in mice greatly increases alveolar bone and tooth dentin mass. We used a bone-targeted recombinant adeno-associated virus (rAAV) carrying an artificial microRNA (miRNA) that silences SHN3 expression to restore alveolar bone loss in mouse models of both postmenopausal and senile osteoporosis by enhancing WNT signaling and osteoblast function. Additionally, rAAV-mediated silencing of SHN3 enhanced bone formation and collagen production of human skeletal organoids in xenograft mice. Finally, rAAV expression in the mandible was tightly controlled via liver- and heart-specific miRNA-mediated repression or via a vibration-inducible mechanism. Collectively, our results demonstrate that AAV-based bone anabolic gene therapy is a promising strategy to treat alveolar bone loss in osteoporosis.
PubMed: 38937970
DOI: 10.1016/j.ymthe.2024.06.036 -
Seminars in Nuclear Medicine Jun 2024Radiopharmaceutical approaches for targeting bone metastasis have traditionally focused on palliation of pain. Several agents have been clinically used over the last... (Review)
Review
Radiopharmaceutical approaches for targeting bone metastasis have traditionally focused on palliation of pain. Several agents have been clinically used over the last several decades and have proven value in pain palliation providing pain relief and improving quality of life. The role is well established across several malignancies, most commonly used in osteoblastic prostate cancer patients. These agents have primarily based on targeting and uptake in bone matrix and have mostly included beta emitting isotopes. The advent alpha emitter and FDA approval of 223Ra-dichloride has created a paradigm shift in clinical approach from application for pain palliation to treatment of bone metastasis. The approval of 223Ra-dichloride given the survival benefit in metastatic prostate cancer patients, led to predominant use of this alpha emitter in prostate cancer patients. With rapid development of radiopharmaceutical therapies and approval of other targeted agents such as 177Lu-PSMA the approach to treatment of bone metastasis has further evolved and combination treatments have increasingly been applied. Novel approaches are needed to improve and expand the use of such therapies for treatment of bone metastasis. Combination therapies with different targeting mechanisms, combining chemotherapies and cocktail of alpha and beta emitters need further exploration.
PubMed: 38937221
DOI: 10.1053/j.semnuclmed.2024.05.006 -
In Vivo (Athens, Greece) 2024Recent reports indicate that sclerostin is secreted by periodontal ligament tissue-derived (PDL) cells during orthodontic force loading and that the secreted sclerostin...
BACKGROUND/AIM
Recent reports indicate that sclerostin is secreted by periodontal ligament tissue-derived (PDL) cells during orthodontic force loading and that the secreted sclerostin contributes to bone metabolism. However, the detailed mechanism is poorly understood. The aim of this study was to determine how PDL cells affect bone formation.
MATERIALS AND METHODS
Rat periodontal ligament tissue was immunohistochemically stained for sclerostin. Cultured primary PDL cells, osteoblasts, and skin fibroblasts (Sfbs) isolated from rat periodontal ligament tissue, calvaria, and skin, respectively, were examined. Osteoblasts were cultured with control conditioned medium (Cont-CDM) and PDL cell culture conditioned medium (PDL-CDM) for up to 21 days. Cultured osteoblasts were then stained with alkaline phosphatase and von Kossa stain. Osteoblasts cultured in each conditioned medium were analyzed by real-time quantitative PCR for bone Gla protein (Bgp), Axin2, and Ki67 expression. PDL cells used to obtain conditioned medium were analyzed for Sost, Ectodin and Wnt1 expression and compared with expression in Sfbs.
RESULTS
Expression of sclerostin was observed in periodontal ligament tissue by immunohistochemical staining. The formation of mineralization nodules was inhibited in PDL-CDM compared with Cont-CDM in osteoblast culture. In PDL-CDM, the expression levels of Bgp and Axin2 in osteoblasts were decreased compared with Cont-CDM. In PDL cells, expression levels of Sost and Ectodin were much higher than in Sfbs; however, expression of Wnt1 was lower in PDL cells compared with Sfbs.
CONCLUSION
PDL cells secrete various proteins, including sclerostin and suppress osteogenesis in osteoblasts through the canonical Wnt pathway.
Topics: Periodontal Ligament; Animals; Osteogenesis; Osteoblasts; Rats; Culture Media, Conditioned; Cells, Cultured; Male; Fibroblasts; Cell Differentiation; Immunohistochemistry; Bone Morphogenetic Proteins; Genetic Markers
PubMed: 38936890
DOI: 10.21873/invivo.13609 -
Biochemical and Biophysical Research... Jun 2024With the aging of the global demographic, the prevention and treatment of osteoporosis are becoming crucial issues. The gradual loss of self-renewal and osteogenic...
With the aging of the global demographic, the prevention and treatment of osteoporosis are becoming crucial issues. The gradual loss of self-renewal and osteogenic differentiation capabilities in bone marrow stromal cells (BMSCs) is one of the key factors contributing to osteoporosis. To explore the regulatory mechanisms of BMSCs differentiation, we collected bone marrow cells of femoral heads from patients undergoing total hip arthroplasty for single-cell RNA sequencing analysis. Single-cell RNA sequencing revealed significantly reduced CRIP1 (Cysteine-Rich Intestinal Protein 1) expression and osteogenic capacity in the BMSCs of osteoporosis patients compared to non-osteoporosis group. CRIP1 is a gene that encodes a member of the LIM/double zinc finger protein family, which is involved in the regulation of various cellular processes including cell growth, development, and differentiation. CRIP1 knockdown resulted in decreased alkaline phosphatase activity, mineralization and expression of osteogenic markers, indicating impaired osteogenic differentiation. Conversely, CRIP1 overexpression, both in vitro and in vivo, enhanced osteogenic differentiation and rescued bone mass reduction in ovariectomy-induced osteoporosis mice model. The study further established CRIP1's modulation of osteogenesis through the Wnt signaling pathway, suggesting that targeting CRIP1 could offer a novel approach for osteoporosis treatment by promoting bone formation and preventing bone loss.
PubMed: 38936225
DOI: 10.1016/j.bbrc.2024.150277 -
Clinical Neurology and Neurosurgery Mar 2024Primary intraosseous meningioma of the skull (PIMS) is a rare type of primary extradural meningioma (PEM) involving cranial bone. The existing literature strongly...
BACKGROUND
Primary intraosseous meningioma of the skull (PIMS) is a rare type of primary extradural meningioma (PEM) involving cranial bone. The existing literature strongly suggest the importance of radiological feacures in pathological diagnosis of PIMS. Thereby, the aim of this study is to investigate the association between imaging classification and histopathological grading in PIMS.
METHODS
In this retrospective study, we retrospectively analyzed the computed tomography scan/magnetic resonance imaging and pathological data pertaining to patients with pathologically proven PIMS. The association between radiological features, imaging classification, and histopathological grading was analyzed using logistic regression analysis.
RESULTS
In this study, data of 25 patients with PIMS were assessed. The univariate logistic regression analysis results showed significant correlation between histopathological grading and imaging classification (OR: 22.5; 95% CI: 2.552-198.378; p = 0.005), intra- and extracalvarial extension (OR: 7.2; 95% CI: 1.066-48.639; p = 0.043), and tumor margin (OR: 7.19; 95% CI: 1.06-47.61; p = 0.043). According to the results of multivariate logistic regression analysis, imaging classification was the strongest independent risk factor for high-grade PIMS, and the risk of aggressiveness of osteoblastic type of PIMS was 16.664 times higher than that of osteolytic type of PIMS (OR: 16.664; 95% CI: 1.15-241.508; p = 0.039).
CONCLUSIONS
Imaging classification is an independent risk factor for high-grade PIMS.
PubMed: 38936174
DOI: 10.1016/j.clineuro.2024.108239 -
Advanced Biology Jun 2024New-QiangGuYin (N-QGY), the addition of sea buckthorn on the basis of QGY formula, is herbal formula widely used clinically in China for the treatment of osteoporosis...
New-QiangGuYin (N-QGY), the addition of sea buckthorn on the basis of QGY formula, is herbal formula widely used clinically in China for the treatment of osteoporosis (OP), but its mechanism warrants further exploration. The mechanisms of QGY and N-QGY in the treatment of OP are probed from the perspective of osteoclast-osteoblast balance. Thirty Sprague-Dawley rats are randomly divided into N-QGY group, QGY group, and Control group. Beyond control rats that orally took normal saline, other rats are orally administered with isometric N-QGY or QGY twice every day for 3 days. The drug-containing serum and control serum are prepared and their effects on osteoclast-derived exosome secretion are determined by bicinchoninic acid assay (BCA), nanoparticle tracking analysis, and Western blot. GW4869 and Interleukin-1β (IL-1β) are adopted as the exosome inhibitor and inducer, respectively. Exosome uptake, cell counting kit-8, alkaline phosphatase (ALP) staining, alizarin red staining, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and Western blot are performed to examine the effects of altered osteoclast exosome content on osteogenic differentiation of mesenchymal stem cells (MSCs). N-QGY, QGY, and GW4869 inhibit osteoclast-derived exosome secretion and exosome uptake by MSCs, whereas IL-1β exerted the opposite effects (p < 0.05). Different from IL-1β, N-QGY, QGY, and GW4869 partially elevated MSC viability, osteocalcin secretion, ALP, RUNX Family Transcription Factor 2 (RUNX2) and Osteopontin (OPN) expressions, and calcium deposition in the osteoclast-MSCs coculture system (p < 0.05). Mechanically, osteoclasts increased Notum protein level but decreased β-catenin level, which is enhanced by IL-1β but is reversed by GW4869, QGY, and N-QGY (p < 0.05). And the effect of N-QGY is more conspicuous than that of QGY (P<0.05). N-QGY-containing serum inhibits exosome levels in osteoclasts, thereby enhancing osteogenic differentiation of MSCs via inhibition of Notum protein and promotion of β-catenin protein.
PubMed: 38935529
DOI: 10.1002/adbi.202400166 -
Amino Acids Jun 2024Exogenous polyamines, including putrescine (PUT), spermidine (SPD), and spermine (SPM), and the irreversible inhibitor of the rate-limiting enzyme ornithine...
Exogenous polyamines, including putrescine (PUT), spermidine (SPD), and spermine (SPM), and the irreversible inhibitor of the rate-limiting enzyme ornithine decarboxylase (ODC) of polyamine biosynthesis, α-difluoromethylornithine (DFMO), are implicated as stimulants for bone formation. We demonstrate in this study the osteogenic potential of exogenous polyamines and DFMO in human osteoblasts (hOBs), murine monocyte cell line RAW 264.7, and an ovariectomized rat model. The effect of polyamines and DFMO on hOBs and RAW 264.7 cells was studied by analyzing gene expression, alkaline phosphatase (ALP) activity, tartrate-resistant acid phosphatase (TRAP) activity, and matrix mineralization. Ovariectomized rats were treated with polyamines and DFMO and analyzed by micro computed tomography (micro CT). The mRNA level of the early onset genes of osteogenic differentiation, Runt-related transcription factor 2 (Runx2) and ALP, was significantly elevated in hOBs under osteogenic conditions, while both ALP activity and matrix mineralization were enhanced by exogenous polyamines and DFMO. Under osteoclastogenic conditions, the gene expression of both receptor activator of nuclear factor-κB (RANK) and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) was reduced, and TRAP activity was suppressed by exogenous polyamines and DFMO in RAW 264.7 cells. In an osteoporotic animal model of ovariectomized rats, SPM and DFMO were found to improve bone volume in rat femurs, while trabecular thickness was increased in all treatment groups. Results from this study provide in vitro and in vivo evidence indicating that polyamines and DFMO act as stimulants for bone formation, and their osteogenic effect may be associated with the suppression of osteoclastogenesis.
Topics: Animals; Mice; Osteoclasts; Osteogenesis; Rats; Humans; Cell Differentiation; Eflornithine; Female; Polyamines; Osteoblasts; RAW 264.7 Cells; Ovariectomy; Rats, Sprague-Dawley; Spermidine
PubMed: 38935136
DOI: 10.1007/s00726-024-03403-8 -
Endocrinology Jun 2024Thyroid hormone (TH) plays a crucial role in regulating the functions of both bone and adipose tissue. Given that TH exerts its cholesterol-lowering effects in hepatic...
Thyroid hormone (TH) plays a crucial role in regulating the functions of both bone and adipose tissue. Given that TH exerts its cholesterol-lowering effects in hepatic tissue through the TH receptor-β (TRβ), we hypothesized that TRβ agonist therapy using MGL3196 (MGL) would be effective in treating increased adiposity and bone loss in response to a 12-week high-fat diet (HFD) in adult C57BL/6J mice. Transcriptional and serum profiling revealed that HFD-induced Leptin promoted weight gain in both males and females, but MGL only suppressed Leptin induction and weight gain in males. In vitro studies suggest estrogen suppresses MGL activity in adipocytes, indicating estrogen might interfere with MGL-TRβ function. Compared to systemic adiposity, HFD reduced bone mass in male but not female mice. Paradoxically, MGL treatment reversed macroscopic BMD loss in appendicular bones, but micro-CT revealed that MGL exacerbated HFD-induced trabecular bone loss, and bone strength. In studies on the mechanisms for HFD effects on bone, we found that HFD induced Rankl expression in male femurs that was blocked by MGL. By ex vivo assays, we found that RANKL indirectly represses osteoblast lineage allocation of osteoprogenitors by induction of inflammatory cytokines TNFα, Il-1β, and CCL2. Finally, we found that MGL functions in both systemic adiposity and bone by nongenomic TRβ signaling, as HFD-mediated phenotypes were not rescued in TRβ147F knockout mice with normal genomic but defective nongenomic TRβ signaling. Our findings demonstrate that the negative effects of HFD on body fat and bone phenotypes is impacted by MGL in a gender-specific manner.
PubMed: 38935021
DOI: 10.1210/endocr/bqae075