Naibedya Chattopadhyay

The Wnt/β‐catenin signaling pathway is pivotal for osteoblast differentiation, bone formation, and skeletal homeostasis, with its dysregulation linked to osteoporosis and fracture non‐union. Phytochemicals offer promising alternatives to unstable Wnt ligands, which risk tumorigenesis due to non‐specific activation. In this study, we performed an extensive computational screening of selected phytochemicals—including quercetin, kaempferol, apigenin, genistein, gallic acid, ursolic acid, 2α‐hydroxy ursolic acid, and berberine—previously reported to modulate the Wnt/β‐catenin pathway. These compounds, derived from diverse phytochemical classes including flavonoids, isoflavones, phenolic acids, triterpenoids, and alkaloids, have been shown in prior experimental studies to promote osteogenic responses by stabilizing β‐catenin, inhibiting GSK‐3β, and upregulating osteogenic genes such as Axin2 and cyclin D1 . To complement these findings, we employed computational approaches, including gene–drug interaction analysis (DGIdb), structural similarity screening (Data Warrior, > 90% similarity to known drugs), and molecular docking (Maestro Schrödinger Suite), to predict high‐affinity interactions with key regulatory proteins in the Wnt pathway. Our docking results revealed high binding affinities of phytochemicals to key targets that are involved in the modulation of the Wnt/β‐catenin pathway, such as Casein Kinase (CK, docking scores: −10.652 to −11.39), Estrogen Receptor (ER, docking score: −7.337 to −11.314), Vitamin D Receptor (VDR, docking score: −7.40 to −9.97), and GSK‐3β, with critical interactions involving residues like E305 and R346. Specifically, Caviunin glycoside from Dalbergia sissoo demonstrated estrogenic modulation within the ER ligand‐binding domain (PDB ID: 1X7J; docking score: −5.29), supporting its role in osteoblast stimulation via ER‐Wnt crosstalk. Structure–activity analyses identify flavanone glycosides and triterpenoids as promising scaffolds for medicinal chemistry optimization. Challenges, including poor bioavailability and off‐target effects, necessitate advanced delivery systems and computational modeling to enhance selectivity and therapeutic utility, positioning these phytochemicals as viable leads for bone‐related disorder treatments.

Temozolomide (TMZ) is a frontline chemotherapeutic agent for glioblastoma multiforme (GBM); however, approximately half of patients develop resistance to therapy. This study investigates the role of altered cellular bioenergetics and metabolism in the acquired TMZ resistance. Using untargeted metabolomics, we explored the metabolic rewiring in TMZ-resistant GBM cells and identified key alterations in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, and amino acid metabolism, all might be linked to cellular proliferation. Our findings suggest that while glycolysis remains important, increased TCA cycle activity contributes to the drug resistance, supported by increased levels of mitochondrial mass and mitochondrial membrane potential. We observed significantly elevated glutamine levels, which may enhance mitochondrial activity, thereby supporting increased energy production. Furthermore, resistant cells exhibited enhanced NRF2 level in parallel with higher levels of antioxidants, including glutathione and catalase enzyme, and a concomitant decrease in the level of its negative regulator, KEAP1. These factors collectively may contribute to drug resistance by mitigating oxidative stress. These findings indicate that mitochondrial metabolic reprogramming and NRF2/KEAP1-mediated antioxidant defense mechanisms play a crucial role in TMZ resistance, and targeting these pathways may offer a novel strategy to overcome resistance in GBM therapy.

Purpose Isovitexin is an agonist of adiponectin receptors (AdipoRs). Adiponectin has been shown to have beneficial effects on bone and muscle function, in addition to its positive impact on metabolic health. However, the preclinical and clinical application of adiponectin faces scalability challenges, prompting the investigation of isovitexin in a methylprednisolone (MP)-induced osteoporosis model. Methods A rat model of MP-induced osteoporosis was developed to evaluate isovitexin’s effects on bone health, including bone mass & microarchitecture (MicroCT), turnover markers (P1NP and CTX-1), strength (three-point bending, and nanoindentation), and quality (FTIR). We also investigated the muscle protective effects of isovitexin by measuring key muscle catabolic (atrogenes) proteins. Results Isovitexin effectively prevented MP-induced osteopenia in critical weight-bearing, fracture-prone sites, such as the proximal femur and lumbar vertebrae. Bone turnover markers revealed its osteogenic and anti-resorptive properties, crucial for countering glucocorticoid-induced bone loss. Isovitexin treatment preserved the mineral and material composition of bone, indicating that it helps maintain the tissue integrity and mechanical strength. Hitherto observed effects of isovitexin likely resulted in the preservation of bone quality, demonstrated by preserving mechanical behavior and bone strength, which are essential for preventing fractures. MP treatment led to muscle atrophy, evidenced by reduced gastrocnemius diameter and cross-sectional area. Isovitexin countered these effects and inhibited atrogenes (atrogin-1 and MuRF-1) induction. Conclusion Isovitexin not only mitigates osteopenia but also maintains overall bone quality and composition, exhibiting dual osteogenic and anti-resorptive effects. Its capacity to reduce muscle atrophy underscores its potential as a comprehensive treatment for glucocorticoid-induced osteoporosis and sarcopenia.

Introduction Hyperphosphatemia leads to abnormal mineralization of bones and soft tissues in patients with chronic kidney disease-induced secondary hyperparathyroidism (CKD-SHPT). Sevelamer lowers phosphate levels by binding to dietary phosphate in the gastrointestinal system, forming new bone and reducing the risk of renal osteodystrophy and fracture. However, the influence of sevelamer carbonate (SevC) on bone microarchitecture, material qualities, and mechanical behavior is unknown in CKD-SHPT conditions. Material and methods We utilized a rat model of CKD-induced hyperphosphatemia by feeding a 1.8% high-phosphate diet to 5/6 nephrectomized rats to test the effects of SevC on skeletal quality and strength, employing microCT, Fourier transform infrared spectroscopy (FTIR), 3-point bending, nanoindentation, and compression tests. Results SevC preserved mineral homeostasis and reduced PTH, and FGF-23 levels in CKD-SHPT rats. SevC mitigated the serum renal parameters, pyrophosphate levels, and indole acetic acid. In CKD-SHPT rats, SevC reduced hyperphosphatemia, improved the mineralization defect, and upregulated mineralization-promoting genes like ankyrin-1, ectonucleotide-pyrophosphatase/phosphodiesterase-1, tissue non-specific alkaline phosphatase, phosphate-regulating endopeptidase X-linked, dentin matrix protein-1, and matrix extracellular phosphoglycoprotein. In the cortical bones of CKD-SHPT rats, SevC increased cortical mass and thickness, decreased porosity by likely decreasing cortical bone remodeling induced by high PTH, and increased osteocyte preservation. SevC mitigated all of the alterations in the mineral and matrix composition of CKD-SHPT rats, including decreased collagen-maturity, mineral-to-matrix ratio, and increased carbonate substitution of hydroxyapatite crystals. SevC enhanced bone strength and mechanical behavior in CKD-SHPT rats at a macro (three-point bending) and nano (nanoindentation) scales. Conclusion These findings in CKD-SHPT rats suggest that SevC improves bone mechanical properties at various levels by decreasing serum pyrophosphate, empty lacunae, and enhancing renal clearance of indole acetic acid, organized mineral-matrix deposition, and osteocyte number by suppressing cortical remodeling.

Various metabolic abnormalities, including obesity, insulin resistance, hypertension, dyslipidemia, hyperthyroidism and low vitamin D levels, have been linked to both osteopenia and sarcopenia. Osteosarcopenia is also commonly observed in older age groups, notably in postmenopausal women. Glucagon-like peptide-1 (GLP-1), a labile incretin secreted from the intestinal L-cells, stimulates insulin secretion and sensitivity, making it an effective anti-diabetic medication. GLP-1 binds to its receptor, the GLP-1 receptor, a G-protein-coupled receptor, and leads to the stimulation of adenylate cyclase, increasing the levels of cyclic AMP (cAMP). Elevated cAMP then activates protein kinase A and other downstream signaling pathways. These signaling cascades result in various cellular responses, such as enhanced insulin secretion from pancreatic beta cells, improved insulin sensitivity and modulation of appetite and gastric emptying. In addition, GLP-1 signaling can promote cell growth and survival, contributing to its effects on muscle and bone health. Its role as an anti-diabetic medication has been enhanced through various modifications to extend its half-life, thereby improving its effectiveness and druggability. GLP-1 analogs, initially developed for diabetes management, have also been harnessed for obesity treatment due to the effect of GLP-1 to induce satiety and slow gastric emptying. Beyond their well-known anti-diabetic and anti-obesity effects, GLP-1 agonists can enhance muscle mass and bone density, making them valuable in addressing conditions such as sarcopenia and osteoporosis. This review focuses on the effects of GLP-1 analogs on musculoskeletal health by critically assessing the underlying signaling mechanisms in order to understand their translational potential for the treatment of osteosarcopenia.

Recent discoveries have established the pivotal role of IL-9-secreting immune cells in a wide spectrum of inflammatory and autoimmune diseases. However, little is known about how IL-9 contributes to the etiology of inflammatory bone loss in PMO. We observed that IL-9 has a pathological impact on inflammatory bone loss in ovariectomized (Ovx) mice. Our in vivo temporal kinetics analysis revealed that estrogen deprivation enhanced the production of IL-9 from Th cells (majorly Th9 and Th17). Both our ex vivo and in vivo studies corroborated these findings in Ovx mice, as estrogen diminishes the potential of Th9 cells to produce IL-9. Mechanistically, Th9 cells in an IL-9-dependent manner enhance osteoclastogenesis and thus could establish themselves as a novel osteoclastogenic Th cell subset. Therapeutically neutralizing/blocking IL-9 improves bone health by inhibiting the differentiation and function of osteoclasts, Th9, and Th17 cells along with maintaining gut integrity in Ovx mice. Post-menopausal osteoporotic patients have increased IL-9-secreting Th9 cells, which may suggest a potential role for IL-9 in the development of osteoporosis. Collectively, our study identifies IL-9-secreting Th9 cells as a driver of bone loss with attendant modulation of gut-immune-bone axis, which implies IL-9-targeted immunotherapies as a potential strategy for the management and treatment of inflammatory bone loss observed in PMO.

Adiponectin, an adipokine, regulates metabolic processes, including glucose flux, lipid breakdown, and insulin response, by activating adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). We have previously shown that globular adiponectin (gAd), an endogenous form of adiponectin, has osteoanabolic and anti-catabolic effects in rodent models of postmenopausal osteopenia. Moreover, we reported the identification of a 13-mer peptide (ADP-1) from the collagen domain of adiponectin, which exhibited significant adiponectin-mimetic properties. Since the clinical development of gAd is constrained by its large size, here, we investigated the osteogenic property of ADP-1. ADP-1 induced osteoblast differentiation more potently than gAd. ADP-1 elicited osteoblast differentiation through two downstream pathways that involved the participation of adiponectin receptors. Firstly, it enhanced mitochondrial biogenesis and OxPhos, leading to osteoblast differentiation. Secondly, it activated the Akt-glycogen synthase kinase 3β-Wnt pathway, thereby increasing osteoblast differentiation. Additionally, ADP-1 suppressed the production of receptor–activator of nuclear kappa B ligand from osteoblasts, enabling it to act as a dual-action molecule (suppressing osteoclast function besides promoting osteoblast function). In osteopenic ovariectomized rats, ADP-1 increased bone mass and strength and improved trabecular integrity by stimulating bone formation and inhibiting bone resorption. Furthermore, by increasing ATP-producing intermediates within the tricarboxylic acid cycle in bones, ADP-1 likely fueled osteoblast function. Given its dual-action mechanism and high potency, ADP-1 offers a unique opportunity to address the unmet clinical need to reset the aberrant bone remodeling in osteoporosis to normalcy, potentially offering a disease-modifying impact.