Martine Cohen-Solal

Background and hypothesis: Denosumab increases bone mineral density (BMD) in dialysis patients, but the effects on bone microarchitecture using high-resolution peripheral quantitative computed tomography (HRpQCT) and the response factors to treatment are unknown. Methods: We analyzed, at a single center between 2014 and 2024, 19 consecutive patients on hemodialysis having a longitudinal HRpQCT monitoring at the distal tibia and radius. After excluding the presence of osteomalacia based on bone biopsies and ensuring well-controlled parathyroid hormone levels, nine patients with recent fractures were treated with denosumab. Changes in HRpQCT parameters observed over time were analyzed within the denosumab group and were compared to a group of a nontreated patients, using linear mixed models for repeated measures. Baseline histomorphometric parameters were analyzed as predictors of changes in HRpQCT parameters over time in denosumab-treated patients. Results: During a median [maximum–minimum] follow-up period of 2.1 [1.0–3.5] years, the nine denosumab-treated patients had a significant improvement of (i) bone volume-to-total volume ratio at the distal radius (+1.63% [95% confidence interval: 1.11–3.31] per year, P = .037) and tibia (+1.13% [0.10–2.28], P = .049), (ii) trabecular volumetric BMD at the distal radius (+1.58 [1.07–3.30], P = .039) and tibia (+0.95% [0.11–1.97], P = .039), (iii) trabecular number at the distal radius (+1.86% [0.45–3.28], P = .017), and (iv) trabecular separation at the distal radius (−1.83% [−3.16 to −0.50], P = .014). These changes were also significant when compared with those of the untreated group. Changes in cortical parameters did not change significantly over time. At most, changes in trabecular volumetric BMD at the radius were negatively associated with osteoid volume. Conclusion: Denosumab improves HRpQCT trabecular bone parameters without significant effect on cortical parameters in dialysis patients.

Endothelial specialization is increasingly recognized as a fundamental regulator of tissue homeostasis, yet the cellular diversity of the skeletal vasculature remains incompletely resolved. Here, we integrate large-scale single-cell transcriptomics, cross-tissue comparisons, and imaging to comprehensively define endothelial heterogeneity across the skeleton. Our analyses demonstrate that the proposed post-arterial "type R" endothelial population is not a distinct endothelial subtype but instead comprises canonical venous endothelial cells and fatty acid-handling endothelial state. RNA velocity supports a venous continuum, while the proposed type R markers FMO2, and AQP7 lack both endothelial and skeletal specificity. The fatty acid-handling endothelial state, characterized by Lpl and Cd36 is conserved across multiple skeletal sites and non-skeletal tissues, indicating a general endothelial metabolic programme. Within bone, this endothelial state expands following high-fat diet and is suppressed during injury. Together, these findings redefine skeletal endothelial heterogeneity and establish the proposed type R population as part of a venous continuum.

Distal-less homeobox genes Dlx5 and Dlx6 are key regulators of osteoblast differentiation during skeletal development, but their role in postnatal bone remodeling remains poorly understood. To investigate this, we conditionally deleted Dlx5/6 in Osterix-lineage cells after 4 wk of birth using an inducible Osx-Cre system. Dlx5/6Δ/Δ Osx-Cre and control mice were analyzed in terms of bone architecture (micro-CT), remodeling (histomorphometry), gene expression profiling, and single-cell RNA sequencing. Postnatal deletion of Dlx5/6 induced a complex skeletal phenotype characterized by radial bone hypertrophy and altered cortical remodeling. Enhanced periosteal activity was associated with increased Osx expression in periosteal cells, confirmed by BaseScope and immunofluorescence analyses. In parallel, cortical bone became thinner and more porous, while trabecular bone displayed reduced bone formation and thinner trabeculae, despite paradoxical accumulation within the diaphysis. These alterations were associated with increased Osx expression in periosteal and diaphyseal compartments, indicating abnormal spatial regulation of osteolineage cell expansion and bone remodeling. Single-cell transcriptomic analysis in BM cells identified altered mesenchymal stromal cell populations with dysregulated extracellular matrix and Wnt signaling pathways, including downregulation of the Wnt antagonist Sfrp1, validated in situ by RNAscope. Consistently, osteoblasts derived from Dlx5/6Δ/Δ Osx-Cre displayed impaired terminal differentiation in vitro, with reduced expression of late osteogenic markers and decreased matrix mineralization. Collectively, these findings identify Dlx5/6 as critical regulators of postnatal bone homeostasis that coordinate osteolineage expansion and terminal osteoblast maturation during postnatal bone remodeling.

The bone marrow niche (BMN) plays a central role in regulating hematopoietic stem-cell (HSC) maintenance, lineage commitment, and immune homeostasis, while also supporting osteogenesis and maintaining skeletal integrity. Once considered static, the BMN is now recognized as a dynamic and responsive microenvironment that integrates local signals and systemic cues to meet physiological demands and respond to stress. Aging causes profound and progressive changes to this niche, leading to functional decline across both hematopoietic and stromal compartments. Recent advances in high-resolution imaging, single-cell and spatial transcriptomics, and in vivo lineage tracing have revealed remarkable heterogeneity and plasticity within the vascular and mesenchymal elements of this niche. Yet, key questions remain unresolved, including the identity and hierarchy of mesenchymal and osteolineage cells, the specialization of subsets of endothelial cells, the integration of systemic regulation, and whether the aging bone marrow acts as a driver or a passenger in malignancy and chronic inflammation. This review revisits current models of the BMN, with a focus on the reciprocal interactions between osteogenic cells and specialized vasculature, and how their disruption during aging impairs hematopoietic output and skeletal remodeling. We also examine how systemic factors such as neural input, metabolic status, and inflammatory signaling influence the aging of the BMN. Finally, we highlight emerging translational platforms, including iPSC-derived bone marrow organoids, engineered niches/hydrogels, and vascularized organ-on-chip systems, that enable mechanistic testing of rejuvenation strategies. Together, these insights have the potential to pave the way toward targeted interventions that restore the function of the BMN and promote healthy aging of the bone and blood systems.

Rare bone disease referral centers (RBDCs) were established to improve the diagnosis and management of rare diseases. The objective of this retrospective observational study was to characterize real-life care pathways of patients with osteogenesis imperfecta (OI) in the Paris region. Patient data were extracted from the Assistance Publique-Hôpitaux de Paris (AP-HP) health data warehouse (Entrepôt de Données de Santé). Patients were identified using the ICD-10 code for OI (Q78.0) and keyword searches. Inclusion criteria were age ≥15 yr and at least one hospital visit between January 1, 2016 and March 1, 2021. After exclusion of unconfirmed diagnoses and patients younger than 15 yr, 472 patients with OI were included (mean age 39.5 ± 16.2 yr; 64.6% women). Of these patients, 78% (N = 368) were cared for in one of Paris RBDC, the majority in a single center (76% (N = 280)), while 104 patients (22%) were not seen within RBDCs in AP-HP data. The most frequent specialties involved were rheumatology (74.9%, N = 326), orthopedics (17.6%, N = 76), and otorhinolaryngology (12.9%, N = 56). The proportion of patients seen in rheumatology increased after the transition age of 25 yr (81.8% before vs 90% after, p = .04), whereas consultations in orthopedics and genetics decreased (29.5% vs 17.8%, p = .02, and 22.7% vs 6.8%, p < .0001, respectively). Orthopedic surgery during follow-up was performed in 6.2% of patients followed in RBDCs and 8.6% of those not seen within RBDCs. Although 78% (N = 368) of patients with OI in the Paris region were followed within RBDCs, nearly one quarter were not (22%), suggesting persistent gaps in access to specialized care. These findings provide a real-life description of hospital-based care pathways for OI but do not allow assessment of the effectiveness of the referral center model.

Autotaxin (ATX/ENPP2) is a lysophospholipase D responsible for lysophosphatidic acid (LPA) production from lysophosphatidylcholine in biological fluids. LPA controls bone metabolism through interplay between specific LPA receptors. However, because Enpp2 deletion causes embryonic lethality, ATX functions within the osteoblast cell lineage and its contributions to bone growth remain undefined. This study shows that expression of Enpp2 is upregulated during osteoblastogenesis and reveales Enpp2 as a target gene of the cAMP signaling pathway. The bone anabolic molecule parathyroid hormone 1–34 fragment (PTH) further increases Enpp2 expression in osteoblasts. Enpp2 expression was significantly higher in bone of transgenic Col1-PPR mice expressing constitutively active PTHR1. PTH treatment elevated circulating ATX levels in mice and hypoparathyroidism patients under PTH therapy. Conditional deletion of Enpp2 in osteoblastic cells (ObDATX) enhanced increased trabecular bone mass and osteoblast activity in response to PTH. Transcriptomic analysis revealed upregulation of bone- and Wnt-related genes in ObDATX mice treated with PTH. In vitro , pharmacological ATX inhibition stimulated osteogenesis, and both pharmacological inhibition and genetic deletion of ATX induced spontaneous accumulation of active β-catenin and transcription of Wnt/β-catenin target genes. These results reveals that ATX as a new negative feed-back regulator of PTH1-34-induced osteogenesis by blocking the Wnt/β-catenin canonical pathway. These data provide insight to a better understanding of mechanism of bone response to PTH and offer a new therapeutic strategy to enhance bone anabolism.