Bone Research最新文献

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.

The discontinuation of denosumab [antibody targeting receptor activator of nuclear factor kappa B ligand (RANKL)] therapy may increase the risk of multiple vertebral fractures; however, the underlying pathophysiology is largely unknown. In patients who underwent discontinuation after multiple injections of denosumab, the levels of tartrate-resistant acid phosphatase 5b increased compared to pretreatment levels, indicating a phenomenon known as “overshoot.” The rate of decrease in bone mineral density during the withdrawal period was higher than the rate of decrease associated with aging, suggesting that the physiological bone metabolism had broken down. Overshoot and significant bone loss were also observed in mice receiving continuous administration of anti-RANKL antibody after treatment was interrupted, resembling the original pathology. In mice long out of overshoot, bone resorption recovered, but osteoblast numbers and bone formation remained markedly reduced. The bone marrow exhibited a significant reduction in stem cell (SC) antigen 1- and platelet-derived growth factor receptor alpha-expressing osteoblast progenitors (PαS cells) and alkaline phosphatase-positive early osteoblasts. Just before the overshoot phase, the osteoclast precursor cell population expands and RANKL-bearing extracellular vesicles (EVs) became abundant in the serum, leading to robust osteoclastogenesis after cessation of anti-RANKL treatment. Thus, accelerated bone resorption due to the accumulation of RANKL-bearing EVs and long-term suppression of bone formation uncoupled from bone resorption leads to the severe bone loss characteristic of denosumab discontinuation.

Age-related osteoporosis poses a significant challenge in musculoskeletal health; a condition characterized by reduced bone density and increased fracture susceptibility in older individuals necessitates a better understanding of underlying molecular and cellular mechanisms. Emerging evidence suggests that osteocytes are the pivotal orchestrators of bone remodeling and represent novel therapeutic targets for age-related bone loss. Our study uses the prematurely aged Polg^D257A/D257A (PolgA) mouse model to scrutinize age- and sex-related alterations in musculoskeletal health parameters (frailty, grip strength, gait data), bone and particularly the osteocyte lacuno-canalicular network (LCN). Moreover, a new quantitative in silico image analysis pipeline is used to evaluate the alterations in the osteocyte network with aging. Our findings underscore the pronounced degenerative changes in the musculoskeletal health parameters, bone, and osteocyte LCN in PolgA mice as early as 40 weeks, with more prominent alterations evident in aged males. Our findings suggest that the PolgA mouse model serves as a valuable model for studying the cellular mechanisms underlying age-related bone loss, given the comparable aging signs and age-related degeneration of the bone and the osteocyte network observed in naturally aging mice and elderly humans.

While bulk RNA sequencing and single-cell RNA sequencing have shed light on cellular heterogeneity and potential molecular mechanisms in the musculoskeletal system in both physiological and various pathological states, the spatial localization of cells and molecules and intercellular interactions within the tissue context require further elucidation. Spatial transcriptomics has revolutionized biological research by simultaneously capturing gene expression profiles and in situ spatial information of tissues, gradually finding applications in musculoskeletal research. This review provides a summary of recent advances in spatial transcriptomics and its application to the musculoskeletal system. The classification and characteristics of data acquisition techniques in spatial transcriptomics are briefly outlined, with an emphasis on widely-adopted representative technologies and the latest technological breakthroughs, accompanied by a concise workflow for incorporating spatial transcriptomics into musculoskeletal system research. The role of spatial transcriptomics in revealing physiological mechanisms of the musculoskeletal system, particularly during developmental processes, is thoroughly summarized. Furthermore, recent discoveries and achievements of this emerging omics tool in addressing inflammatory, traumatic, degenerative, and tumorous diseases of the musculoskeletal system are compiled. Finally, challenges and potential future directions for spatial transcriptomics, both as a field and in its applications in the musculoskeletal system, are discussed.

The SH2 domain-containing protein tyrosine phosphatase 2 (SHP2, also known as PTP2C), encoded by PTPN11, is ubiquitously expressed and has context-specific effects. It promotes RAS/MAPK signaling downstream of receptor tyrosine kinases, cytokine receptors, and extracellular matrix proteins, and was shown in various lineages to modulate cell survival, proliferation, differentiation, and migration. Over the past decade, PTPN11 inactivation in chondrocytes was found to cause metachondromatosis, a rare disorder characterized by multiple enchondromas and osteochondroma-like lesions. Moreover, SHP2 inhibition was found to mitigate osteoarthritis pathogenesis in mice, and abundant but incomplete evidence suggests that SHP2 is crucial for cartilage development and adult homeostasis, during which its expression and activity are tightly regulated transcriptionally and posttranslationally, and by varying sets of functional partners. Fully uncovering SHP2 actions and regulation in chondrocytes is thus fundamental to understanding the mechanisms underlying both rare and common cartilage diseases and to designing effective disease treatments. We here review current knowledge, highlight recent discoveries and controversies, and propose new research directions to answer remaining questions.