Bone Research最新文献

The effectiveness of cranial suture expansion therapy hinges on the timely and adequate regeneration of bone tissue in response to mechanical stimuli. To optimize clinical outcomes and prevent post-expansion relapse, we delved into the underlying mechanisms governing bone remodeling during the processes of suture expansion and relapse. Our findings revealed that in vitro stretching bolstered mesenchymal stem cells’ antioxidative and osteogenic capacity by orchestrating mitochondrial activities, which governed by force-induced endoplasmic reticulum (ER) stress. Nonetheless, this signal transduction occurred through the activation of protein kinase R-like ER kinase (PERK) at the ER-mitochondria interface, rather than ER-mitochondria calcium flow as previously reported. Subsequently, PERK activation triggered TFEB translocation to the nucleus, thus regulating mitochondrial dynamics transcriptionally. Assessment of the mitochondrial pool during expansion and relapse unveiled a sequential, two-phase regulation governed by the ER stress/p-PERK/TFEB signaling cascade. Initially, PERK activation facilitated TFEB nuclear localization, stimulating mitochondrial biogenesis through PGC1-α, thereby addressing energy demands during the initial phase. Subsequently, TFEB shifted focus towards ensuring adequate mitophagy for mitochondrial quality maintenance during the remodeling process. Premature withdrawal of expanding force disrupted this sequential regulation, leading to compromised mitophagy and the accumulation of dysfunctional mitochondria, culminating in suboptimal bone regeneration and relapse. Notably, pharmacological activation of mitophagy effectively mitigated relapse and attenuated bone loss, while its inhibition impeded anticipated bone growth in remodeling progress. Conclusively, we elucidated the ER stress/p-PERK/TFEB signaling orchestrated sequential mitochondria biogenesis and mitophagy under mechanical stretch, thus ensuring antioxidative capacity and osteogenic potential of cranial suture tissues.

Membrane-initiated estrogen receptor α (mERα) signaling has been shown to affect bone mass in murine models. However, it remains unknown which cell types mediate the mERα-dependent effects on bone. In this study, we generated a novel mouse model with a conditional C451A mutation in Esr1, which enables selective knockout of the palmitoylation site essential for the membrane localization of ERα (C451A^f/f). First, we used Runx2-Cre mice to generate Runx2-C451A^f/f mice with conditional inactivation of mERα signaling in Runx2-expressing osteoblast lineage cells. No significant changes were observed in body weight, weights of estrogen-responsive organs, or serum concentrations of estradiol between female Runx2-C451A^f/f and homozygous C451A^f/f littermate controls. High-resolution microcomputed tomography analysis showed a consistent decrease in cortical bone mass in the tibia, femur, and vertebra L5 of Runx2-C451A^f/f mice and three-point bending analysis of humerus revealed an impaired mechanical bone strength in Runx2-C451A^f/f female mice compared to controls. Additionally, primary osteoblast cultures from mice lacking mERα signaling showed impaired differentiation compared to controls. In contrast, conditional inactivation of mERα signaling in hematopoietic cells, by transplantation of bone marrow from mice lacking mERα signaling in all cells to adult wildtype female mice, did not result in any skeletal alterations. In conclusion, this study demonstrates that mERα signaling in osteoblast lineage cells plays a crucial role in the regulation of cortical bone in female mice and shows that mERα inactivation in hematopoietic cells of adult female mice is dispensable for bone regulation.

Rheumatoid arthritis (RA) is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life. RA accelerates musculoskeletal aging, leading to complications such as muscle degeneration and sarcopenia. Recent research has identified myopenia as a condition of significant muscle loss associated with illness, distinct from the muscle wasting seen in other chronic diseases like cancer cachexia or heart failure. In RA, myopenia is characterized by muscle depletion without concurrent significant fat loss, and it can affect individuals of all ages. While inflammation plays a central role, it is not the sole factor contributing to the high incidence of muscle wasting in RA. In subsequent discussions, secondary sarcopenia will be considered alongside myopenia, as both involve muscle wasting decline primarily due to disease. This review summarizes recent findings on the impact of RA-related myopenia and secondary sarcopenia on functional capacity, explores its underlying mechanisms, and discusses contemporary strategies to mitigate the process of musculoskeletal aging in RA patients.

Intervertebral disc degeneration (IDD) is a progressive and dynamic process in which the senescence-associated secretory phenotype (SASP) of nucleus pulposus cells (NPC) plays a significant role. While impaired chaperone-mediated autophagy (CMA) has been associated with inflammation and cellular senescence, its specific involvement in the self-perpetuating feedback loop of NPC senescence remains poorly understood. Through LAMP2A knockout in NPC, we identified a significant upregulation of DYRK1A, a core mediator of premature senescence in Down syndrome. Subsequent validation established DYRK1A as the critical driver of premature senescence in CMA-deficient NPC. Combinatorial transcription factor analysis revealed that under IL1B stimulation or CMA inhibition, elevated DYRK1A promoted FOXC1 phosphorylation and nuclear translocation, initiating transcriptional activation of cell cycle arrest. Intriguingly, CMA impairment concurrently enhanced glutamine metabolic flux in senescent NPC, thereby augmenting their survival fitness. Transcriptomic profiling demonstrated that CMA reactivation in senescent NPC facilitated fate transition from senescence to apoptosis, mediated by decreased glutamine flux via GLUL degradation. Therefore, CMA exerts protective effects against IDD by maintaining equilibrium between premature senescence and senolysis. This study elucidates CMA’s regulatory role in SASP-mediated senescence amplification circuits, providing novel therapeutic insights for IDD and other age-related pathologies.

Rheumatoid arthritis (RA) is a systemic autoimmune disease in which synovial fibroblasts (SFs) maintain chronic inflammation by secreting proinflammatory mediators, leading to joint destruction. While the role of proinflammatory mediators in this process is well-established, the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood. In this study, we investigated the non-inflammatory role of SFs in RA using a co-culture model, and found that SFs from RA patients promote apoptosis of human chondrocytes. Mechanistic investigations reveal that SFs can secrete small extracellular vesicles (sEVs), which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA. sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes. Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis. We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes, exacerbating cartilage damage in vivo. Moreover, chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset. This study suggests that, in RA, the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis, potentially through non-inflammatory regulation, and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.

Itaconate, a macrophage-specific anti-inflammatory metabolite, has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis. We found that itaconate is a TNF-α responsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts. In TNF-transgenic and Irg1^−/− hybrid mice, a more severe bone destruction phenotype was observed. Administration of itaconate prevents excessive activation of osteoclasts by inhibiting Tet2 enzyme activity. Furthermore, exogenous administration of itaconate or its derivative, 4-octyl-itaconate, inhibits arthritis progression and mitigates bone destruction, offering a potential therapeutic strategy for rheumatoid arthritis. This study elucidates that TNF-α drives macrophage-derived itaconate production to epigenetically suppress osteoclast hyperactivation through Tet2 inhibition, establishing itaconate and its derivative OI as novel therapeutic agents against rheumatoid arthritis -associated bone destruction.

Musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis, osteoporosis, bone fracture, intervertebral disc degeneration, tendinopathy, and myopathy, are prevalent conditions that profoundly impact quality of life and place substantial economic burdens on healthcare systems. Traditional bulk transcriptomics, genomics, proteomics, and metabolomics have played a pivotal role in uncovering disease-associated alterations at the population level. However, these approaches are inherently limited in their ability to resolve cellular heterogeneity or to capture the spatial organization of cells within tissues, thus hindering a comprehensive understanding of the complex cellular and molecular mechanisms underlying these diseases. To address these limitations, advanced single-cell and spatial omics techniques have emerged in recent years, offering unparalleled resolution for investigating cellular diversity, tissue microenvironments, and biomolecular interactions within musculoskeletal tissues. These cutting-edge techniques enable the detailed mapping of the molecular landscapes in diseased tissues, providing transformative insights into pathophysiological processes at both the single-cell and spatial levels. This review presents a comprehensive overview of the latest omics technologies as applied to musculoskeletal research, with a particular focus on their potential to revolutionize our understanding of disease mechanisms. Additionally, we explore the power of multi-omics integration in identifying novel therapeutic targets and highlight key challenges that must be overcome to successfully translate these advancements into clinical applications.

Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome (AIDS) patients has remained contentious, with conjectures pointing towards its correlation with distinct antiviral regimes. Protease inhibitors (PIs) stand as a prominent class of antiviral agents frequently utilized in AIDS management and have been significantly linked to premature senescence. This study aimed to investigate whether PI-containing regimens would accelerate osteoarthritis (OA) development and explore the molecular mechanisms underlying this association. A retrospective cohort of 151 HIV-infected individuals, categorized into PI and non-PI groups, was established. Patients in PI group exhibited lower KOOS and a higher prevalence of radiological knee OA than those in non-PI group. Additionally, 25 anti-HIV drugs were screened and among all antiviral drugs, lopinavir had the most detrimental impact on cartilage anabolism, accelerating cartilage senescence and promoting mouse OA development. Mechanistically, lopinavir accelerated cellular senescence by inhibiting Zmpste24 and interfering nuclear membrane stability, which leads to decreased binding between nuclear membrane-binding protein Usp7 and Mdm2 and activates Usp7/Mdm2/p53 pathway. Zmpste24 overexpression reduces OA severity in mice. These findings suggest that PI-containing regimens accelerate cartilage senescence and OA development through Zmpste24 inhibition, which provides new insights into the selection of HIV regimens.

The cranial base synchondroses, comprised of opposite-facing bidirectional chondrocyte layers, drive anteroposterior cranial base growth. In humans, RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with deficient midfacial growth. However, how RUNX2 regulates chondrocytes in the cranial base synchondroses remains unknown. To address this, we inactivated Runx2 in postnatal synchondrosis chondrocytes using a tamoxifen-inducible Fgfr3-creER (Fgfr3-Runx2^cKO) mouse model. Fgfr3-Runx2^cKO mice displayed skeletal dwarfism and reduced anteroposterior cranial base growth associated with premature synchondrosis ossification due to impaired chondrocyte proliferation, accelerated hypertrophy, apoptosis, and osteoclast-mediated cartilage resorption. Lineage tracing reveals that Runx2-deficient Fgfr3⁺ cells failed to differentiate into osteoblasts. Notably, Runx2-deficient chondrocytes showed an elevated level of FGFR3 and its downstream signaling components, pERK1/2 and SOX9, suggesting that RUNX2 downregulates FGFR3 in the synchondrosis. This study unveils a new role of Runx2 in cranial base chondrocytes, identifying a possible RUNX2-FGFR3-MAPK-SOX9 signaling axis that may control cranial base growth.