Bone Research最新文献

Endochondral ossification is a physiological process involving a sequential formation of cartilage and bone tissues. Classically, cartilage and bone formation have been considered independent processes at cellular level. However, the recently described multiple cell differentiation dynamics suggest that some bone cells are indeed the progeny of cartilage cells, or chondrocyte-derived osteoblasts. We hypothesized that the cartilage-to-bone phenotype transition is triggered by specific molecular events. First, the process was assessed in mouse bone tissue, and then, it was mimicked using in vivo cell implantation and in vitro serial differentiation protocols. Data indicates that cartilage cells transition to bone cell phenotype during postnatal physiological bone formation. This process can be reproduced using cartilage precursor cells coupled to specific implantation procedures or differentiation protocols. Gene expression profiling reveals that NOTCH, BMP and MAPK signaling pathways are relevant at the phenotype-switch, while the transcription factors Mesp1, Alx1, Grhl3 and Hmx3 are the feasible driver genes for chondrocyte-derived osteoblasts formation. Altogether, this report shows that endochondral ossification can be modeled using primary cell cultures and data indicate that this process is regulated by specific molecular events, previously described at skeleton morphogenesis during embryo development, and from now on also linkable to postnatal bone development and regeneration processes.

Mitochondrial regulation in mesenchymal stem cells (MSCs) serves as a critical determinant of bone formation and skeletal homeostasis. While dietary nitrate and its transporter Sialin are implicated in systemic homeostasis, their specific roles in MSCs' function remain unclear. Here, we demonstrate that Sialin deficiency impairs MSCs' function and disrupts bone homeostasis. Gain- and loss-of-function studies reveal that Sialin localizes to the mitochondrial membrane and promotes osteogenic differentiation by maintaining mitochondrial bioenergetic integrity. Mechanistically, Sialin recruits pSTAT3^S727 to mitochondria, forming a functional complex that activates mitochondrial bioenergy and stabilizes bone remodeling. Notably, dietary nitrate restores Sialin expression in aged mice, thereby enhancing MSCs' function and preventing osteoporosis. Our findings identify a nutrient-responsive signaling axis-nitrate-Sialin-pSTAT3^S727-that promotes osteogenic differentiation via mitochondrial homeostasis, offering a potential therapeutic strategy for age-related osteoporosis.

Irreversible fibrotic scarring after rotator cuff tear (RCT) compromises the mechanical properties of the healing tendon, yet the underlying mechanisms remain poorly understood. Here, we analyzed the histological features of human RCT scars, characterized by disruption of tendon architecture, disorganized collagen fibrils, and imbalance in type I/III collagen ratios and fibril diameters. Using single-cell RNA sequencing of tendon stumps from patients with RCT, we deconvolved the cellular and molecular landscape of the fibrotic scarring microenvironment. Heterogenous pro-fibrotic subclusters were identified and validated to participate into scar formation, including tendon stem cell, senescent tenocyte, SOX9-driven pro-fibrotic macrophage, and pro-fibrotic endothelial cells undergoing endothelial-mesenchymal transition (EndoMT). Furthermore, we found that osteopontin and TGF-β signaling were key drivers of extracellular matrix deposition, and their blockade ameliorated fibrotic scarring after RCT. Collectively, our study dissected the dynamic scarring microenvironment in human RCT and highlights potential therapeutic targets for preventing pathological scar formation.

Respiratory inflammatory diseases disrupt bone metabolism and cause pathological bone loss. The lung-bone axis is established in chronic diseases like asthma and cystic fibrosis but is less studied in acute lung injury (ALI), recently implicated in COVID-19-induced bone loss. This study examined the effects of LPS-induced ALI on bone phenotype and explored the role of 2-N, 6-O sulfated chitosan (26SCS) in mitigating pneumonia-induced bone loss via inflammatory response modulation. Our findings show that 26SCS effectively reaches bone tissue after oral administration. It promotes macrophage polarization to the M2 phenotype, alleviating immune cascade reactions and inhibiting osteoclast-mediated bone resorption. Increased M2 macrophages support type H vessel formation, enhancing inflammatory bone vascularization. These effects foster a favorable osteogenic microenvironment and mitigate ALI-induced bone loss. While dexamethasone is effective in reducing inflammation, it can aggravate ALI-induced bone loss. Our research offers a therapeutic strategy targeting the lung-bone axis for inflammation-induced bone loss.

Craniofacial development relies on the migration of cranial neural crest cells (CNCCs) to the first and second pharyngeal arches, followed by their differentiation into various cell types during embryogenesis. Although the CNCC migration has been well-studied, the role of the niche in relation to CNCC remains unclear. Variants in FOXI3 have been implicated in craniofacial microsomia (CFM), yet the molecular mechanisms remain unexplored. FOXI3 is expressed in the ectoderm and auricle epidermis, but not in CNCCs or cartilage. Deletion of Foxi3 in the mouse CNCCs did not disrupt mandible and auricular development, further confirming that FOXI3 does not directly regulate CNCCs. However, Foxi3 deficiency in the ectoderm reduced the production of chondrogenesis-related cytokines derived from ectodermal cells, such as TGF-β1. This impairment affected CNCC proliferation through cell communication, subsequently altering the development of the mandible and auricle. These results emphasize the critical role of FOXI3 in establishing the microenvironment supporting CNCC function. Furthermore, FOXI3 directly regulates target genes associated with translation, thereby orchestrating cytokine production in epidermal cells. The validation using auricle sample from a CFM patient carrying FOXI3 mutation further supports our findings. These insights highlight the function of FOXI3 in creating the niche necessary for CNCC development and provide a basis for understanding the molecular mechanisms driving CFM pathogenesis.

Osteoarthritis (OA) is a degenerative skeletal condition marked by the loss of articular cartilage and changes to subchondral bone homeostasis. Treatments for OA beyond full joint replacement are lacking primarily due to gaps in molecular knowledge of the biological drivers of disease. Mass Spectrometry Imaging (MSI) enables molecular spatial mapping of the proteomic landscape of tissues. Histologic sections of human tibial plateaus from knees of human OA patients and cadaveric controls were treated with collagenase III to target extracellular matrix (ECM) proteins prior to MS Imaging of bone and cartilage proteins. Spatial MS imaging of the knee identified distinct areas of joint damage to the subchondral bone underneath areas of lost cartilage. This damaged bone signature extended underneath remaining cartilage in OA joints, indicating subchondral bone remodeling could occur before full thickness cartilage loss in OA. Specific ECM peptide markers from OA-affected medial tibial plateaus were compared to their healthier lateral halves from the same patient, as well as to healthy, age-matched cadaveric knees. Overall, 31 peptide candidates from ECM proteins, including Collagen alpha-1(I), Collagen alpha-1(III), and surprisingly, Collagen alpha-1(VI) and Collagen alpha-3(VI), exhibited significantly elevated abundance in diseased tissues. Additionally, highly specific hydroxyproline-containing collagen peptides, mainly from collagen type I, dominated OA subchondral bone directly under regions of lost cartilage but not areas where cartilage remained intact. A separate analysis of synovial fluid from a second cohort of OA patients found similar regulation of collagens and ECM proteins via LC-MS/MS demonstrating that markers of subchondral bone remodeling discovered by MALDI-MS may be detectable as biomarkers in biofluid samples. The identification of specific protein markers for subchondral bone remodeling in OA advances our molecular understanding of disease progression in OA and provides potential new biomarkers for OA detection and disease grading.

Nociceptive pain is a cardinal feature of traumatic and inflammatory bone diseases. However, whether and how nociceptors actively regulate the immune response during bone regeneration remains unclear. Here, we found that neutrophil-triggered nociceptive ingrowth functioned as negative feedback regulation to inflammation during bone healing. A unique Il4ra⁺Ccl2^high neutrophil subset drove intense postinjury TRPV1⁺ nociceptive ingrowth, which in return dissipated inflammation by activating the production of pro-resolving mediator lipoxin A4 (LXA4) in osteoblasts. Mechanistically, osteoblastic autophagy activated by nociceptor-derived calcitonin gene-related peptide (CGRP) suppressed the nuclear translocation of arachidonate 5-lipoxygenase (5-LOX) to favor the LXA4 biosynthesis. Moreover, in alveolar bone from patients with Type II diabetes, we found diminished nociceptive innervation correlated with reduced autophagy, increased inflammation, and impaired bone formation. Activating nociceptive nerves by spicy diet or topical administration of a clinical-approved TRPV1 agonist showed therapeutic benefits on alveolar bone healing in diabetic mice. These results reveal a critical neuroimmune interaction underlying the inflammation-regeneration balance during bone repairing and may lead to novel therapeutic strategies for inflammatory bone diseases.