Cited by YAP regulates periosteal expansion in fracture repair

What’s New in Musculoskeletal Basic Science DOI

Zbigniew Gugala

Journal of Bone and Joint Surgery, Год журнала: 2024, Номер unknown

Опубликована: Окт. 17, 2024

Musculoskeletal basic science provides a foundation for clinical knowledge while fostering innovation in the management of orthopaedic conditions. In past year, several outstanding articles have been published that advance our understanding neural system function and its crosstalk with immunity tissue healing regulation bone homeostasis, revealing new roles mechanotransduction critically assessing vitamin D supplementation schoolchildren (6 to 13 years age). Novel research was generated on maintaining muscle strength function, establishing role synovium chronic inflammatory joint pathology, effects aging musculoskeletal system. These publications provide insight into physiologic pathologic processes underlying conditions assess routine practices high-level evidence. All 20 chosen this review were extremely prestigious, high-impact-factor journals. Somatic Autonomic Innervation Physical activity requires precisely coordinated participation somatic nervous controlling skeletal muscles autonomic enabling synchronous responses from inner organs. Although innervations separate anatomic representations, nature their interactions remains elusive. Zhang et al.1 discovered spinal-projecting neurons rostral ventromedial medulla (rVMM) simultaneously coregulate both motor sympathetic different bodily functional states. Using adeno-associated virus (AAV) retrograde tracing optogenetic mapping, located gigantocellular reticular nucleus alpha (GiA) ventral part (GiV) rVMM exhibited axon collaterals connecting spinal neurons. excitatory or inhibitory tone concurrently (blood pressure, heart rate). Active states such as exercise neuron excitation causing high tones, whereas quiescent sleep showed inhibition yielding atonia hypoactivity. This study considerably advances neuronal circuitry governing during Neuroimmune Modulation Tissue Healing Nociceptive sensory are important immunoregulators exerting protective damaging via neurogenic inflammation. The neuroimmune following an injury poorly understood. Lu al.2 demonstrated ablation Nav1.8 voltage-gated sodium channels nociceptive dorsal root ganglia (DRG) impaired full-thickness skin wounds regeneration volumetric loss. Transgenic Nav1.8cre/Rosa26DTA mice lacking exhibit ingrowth granulation tissue, which coincides local downregulation calcitonin gene-related peptide (CGRP). CGRP released by Nav1.8+ enables interacting CD11b+ myeloid cells receptor activity-modifying protein 1 (RAMP1). upregulates thrombospondin-1 (TSP-1) neutrophils monocytes/macrophages inhibit recruitment enhance efferocytosis M2 polarization. Mice diabetic neuropathy (Leprdb/db), similar Nav1.8-deficient mice, reduced expression tissue-healing, can be mitigated exogenous delivery. tissue-healing involves complex CGRP-mediated suggested potential treatment options. Regulation Bone Homeostasis A demand calcium levels breast milk lactation causes abrupt mechanistic studies, Babey al.3 identified cellular communication network factor 3 (CCN3) potent osteoanabolic hormone early postpartum period throughout lactation. CCN3 is secreted kisspeptin-positive arcuate (ARCKISS1+) brain. Parabiosis female wild-type overexpressing (Esr1Nkx2-1-cre) revealed same mass. Further, human stem exposed enhanced osteogenic differentiation matrix mineralization, regardless cell donor age sex. Systemic delivery augmented phenotype ovariectomized reversed sequelae high-fat diet known compromise ARCKISS1+ Finally, localized femoral osteotomy aged male mice. Knocking down Ccn3 leads excessive loss lactation, further compounded low-calcium diet. maternal brain-derived, osteoprotective delineated properties. Osteoclastogenesis controls turnover, although pathways regulating process remain unclear. Colocalization osteoclast precursors eosinophils marrow suggests interaction. Andreev al.4 regulate normal Eosinophil-deficient ΔdblGATA knockout marked reduction mass due increased osteoclastogenesis. Conversely, eosinophilia transgenic interleukin (IL)-5 strongly inhibits altering transcriptional profile. Eosinophil peroxidase (EPX) regulator formation downregulating mitochondrial reactive oxygen species (ROS) mitogen-activated kinases (MAPKs) precursors. EPX ameliorated induced arthritis estrogen deprivation. humans, number highly correlated healthy participants patients rheumatoid arthritis. novel homeostasis underscored innate process. Mechanotransduction Development, Health, Disease Postnatally, mechanical signals dynamically adaptive changes; however, cues embryonic development largely unknown. Collins al.5 established essential Hippo signaling downstream transcription factors YAP (Yes-associated protein) TAZ (transcriptional coactivator PDZ-binding motif) fetal murine osteoblasts endothelial endochondral ossification form bone. selective YAP/TAZ deletion osterix (Osx)-expressing mechanoresponsivness alteration gene required cytoskeleton rearrangement sense stimuli. spatially couple Osx+ osteoblast sprouting vessels initiate cartilage hypertrophy remodeling at centers, thereby mechanoregulating developing limbs. Single-cell transcriptomics specific population vessel-associated precursors, these downregulated C-X-C motif chemokine 12, mediates vascular morphogenesis. Ex vivo bioreactor-based stimulation explanted (E15.5) mouse hindlimbs abrogated load-induced osteogenesis sites. reveals key mechanosignaling development, implications pathologies associated akinesia hypokinesia uterine crowding. Daylight primary entrainer circadian rhythms, pacing resetting Food intake, ambient temperature, stress uncouple rhythms autonomous organ levels. study, Dudek al.6 cyclic loading resultant osmolarity changes reset rhythm phase amplitude head articular intervertebral disc devoid innervation vascularity. treadmill PER2::Luc reporter they hyperosmolarity alone effectively shift internal clock young phenotypes modulating genes. Transcriptomic biochemical analyses PLD2-mTORC2-AKT-GSK3β molecular pathway convergent mechanism mediating loading-induced hyperosmolarity-induced entrainments. results demonstrate mechanoresponsiveness synchronizing suggest osmolar intervention Altered implicated fragility type-2 diabetes mellitus detrimental high-glucose osteocytes. Shao al.7 unilateral tibial (1,200 cycles per day 2 weeks) fails improve mass, microarchitecture, genetically spontaneous (KK-Ay) high-fat-diet combined streptozotocin (HFD/STZ)-induced mellitus. lack directly attenuated Ca2+ oscillatory dynamics osteocytes mediated SERCA2 pump. peroxisome proliferator-activated α (PPARα), leading fewer weaker spikes prolonged uptake phenotype. loading-dependent oscillations cause immediate actin contractions, osteocyte secretory activities (RANKL, OPG, SOST). istaroxime, agonist, improves rescuing models. Similarly, conditional osteocyte-specific overexpression (SERCA2flox/flox; DMP1-Cre) mellitus-related suppression mechanoresponsiveness. provided compromised signatures druggable targets. Its Blood Supply Transcortical connect endosteum periosteum permit molecule trafficking between medullary external compartments across osteocyte-populated cortex. Liao al.8 unique osteocytes, which, rich direct dendritic connections transcortical vessels, transfer mitochondria protect them oxidative stress, promote proliferation migration, enhancing vessel formation. (Dmp1Cre-DTAki/wt) exhibits substantial density connectivity, resulting significant downexpression angiogenic genes (Vegfc, Slit3, Notch3, Notch4). osteocyte-endothelium Dendra2-labeled visualized vitro functionality. metabolic involved induction D-sphingosine catalyzed sphingosine kinase (SPHK1). osteocyte-derived (2 mg/kg 7 days) intact density, diaphyseal defect findings identify homeostasis. orchestrating migration bone-healing thorough understanding. dynamic imaging Bixel al.9 employed intravital multiphoton microscopy longitudinally surveil vascularization calvarial determined initial microvessel (CD31+ Emcn+) did not temporally associate osteoprogenitors (Osx+ Runx2+) emerging periosteum. Second-harmonic generation permitted simultaneous visualization angiogenesis double-transgenic Flk1-GFP SP7-mCherry early-formed adjacent uninjured but rather outer periosteal meningeal vasculature, blood flow velocities variable independent diameter. Compared fracture-healing, uncoupling healing. contrast angiogenesis-related hypoxia-related (Hif1a, Vegfa, Angpt2) only slightly expressed healing, surprisingly, profoundly altered ingrowth, Notch growth (VEGF) affect represented pioneering effort sequential entire repair multiscale level relationships osteogenesis. Vitamin Supplementation Schoolchildren promoting specifically growing skeleton. Severe deficiency rickets therapy; children lacks Recently, sister subtrials reported, nested within main Phase-3 randomized trials (RCTs). subtrial Ganmaa al.10 involving secondary analysis outcomes RCT conducted Mongolia, 8,851 age) receive weekly oral 14,000-IU D3 (4,418 schoolchildren) placebo (4,433 fracture incidence assessed. At baseline, 31.9% D-deficient (<25 nmol/L), 63.5% D-insufficient (25 50 4.4% D-sufficient (>50 nmol/L). trial end point, group had normalized (mean, 72.1 whereas, group, status remained insufficient (26.1 nmol/L); nevertheless, (6.4%) compared (6.1%). Alterations parathyroid (PTH), alkaline phosphatase (ALP), minerals noted children. Middelkoop al.11 ViDiKids assessed effect 10,000-IU mineral content (BMC) serum calcium, D3, PTH levels, markers (ALP, C-terminal telopeptide type I collagen [CTX], procollagen N-propeptide [P1NP]), 450 Black African 11 South Africa. 5.8% participating (<50 and, higher (mean difference, 39.9 lower 0.55 pmol/L). There no differences BMC dual x-ray absorptiometry (DXA) (whole body less head; lumbar spine), turnover markers. Fracture very low groups (0.93% 1.32%). null indicate does reduce fractures despite insufficiency. Maintaining Skeletal Muscle Strength Function health benefits intentional weight offset lowering (BMD) increasing may concerning older individuals. Jensen al.12 reported determine hip, spine, forearm after 8-week diet-induced followed 52-week maintenance intervention. 195 eligible (124 71 male, 18 65 age, index 32 43 kg/m2, diabetes, least 5% diet) equally (1) supervised moderate-to-vigorous-intensity program; (2) glucagon-like peptide-1 agonist (liraglutide, 3.0 mg daily); (3) liraglutide; (4) placebo. Unlike (+6.1 kg), all sustained fat reductions, greatest exercise-liraglutide (−16.9 kg). BMDs remined unchanged liraglutide hip spine more than alone, effects. (P-CTX, P-P1NP) initially later normalized. combination achieve effective without compromising health. Patients accumulate subcutaneously, viscerally, intramuscularly, insulin resistance cardiometabolic risks. Increased intramyocellular also occurs endurance athletes who insulin-sensitive, athlete's paradox. Mezincescu al.13 parallel, nonrandomized compare myocyte lipid signature vastus lateralis age-matched (n = 27; metformin; sedentary lifestyle) 29; cycling/running/triathlon; ≥5 training ≥420 min/week) before deconditioning. 1H-magnetic resonance spectroscopy, stable isotope U-13C tracing, biopsy lipidomics unsaturated blunted palmitate linoleate kinetics, saturation kinetics. rendered values comparable those 4-week deconditioning athletes, improved sensitivity, cholesterol triglycerides, glycemic control, physical performance, sensing. mellitus-modifying reverse maladapted accumulation mitigate resistance. Loss elderly disability frailty. Despite high-protein diet, adults notable anabolic (anabolic resistance), Ni Lochlainn al.14 double-blinded, placebo-controlled (the PROMOTe trial) investigate gut microbiome cognition adults. 72 (56 16 male; 36 sets twins ≥60 [mean, 73 (range, 63 83 years)]), who, each pair, prebiotics daily 12 weeks Both additionally underwent received branched-chain amino acids. changed taxa, difference (5-repetition chair raise time; grip strength; Short Performance Battery; International Activity Questionnaire [IPAQ] MET minutes) noted. However, improvement cognitive first-factor score support gut-brain axis concept use interventions population. Role Synovium Arthritis site inflammation osteoarthritis stages eventual destruction. Jiang al.15 integrated genomics chromatin accessibility mapping comprehensive profile synovium, offering insights genetic regulatory mechanisms predisposition. analyzed genotype data obtained 245 (Chinese ethnicity; 77 168 patients; 46 84 age), knee replacement. It 4,765 616 cis-expression quantitative trait loci (cis-eQTLs) eQTLs multiple stronger heritability single eQTLs. By integrating genome-wide association (GWAS) eQTLs, osteoarthritis-related identified, 38 novel. Epigenetic variants affecting 1,517 regions detected. Among top 10 eQTL enriched transcription-factor-binding sites, (PAX5, TCF3, ELF1, REL, IRF4, YY1, NFKB2) immune pathways. offered most extensive resource date, paving way future research. Chronic infiltration various hallmark synovial pathology Mast characteristic; Lei al.16 microenvironment mast activation degranulation MAS-related G protein-coupled X2 (MRGPRX2) major histocompatibility (MHC) class II (MHC II) costimulatory molecules CD4+ T-cell response. osteoarthritis, frequency aggregation severity. Furthermore, adoptive promoted disease progression collagen-induced (CIA) cromolyn anti-IL-17A, membrane stabilizers, markedly pathology. indicated targeting option. System Aging men moderate hypogonadism aging, testosterone health; reducing clear. Snyder al.17 TRAVERSE whether prevent mild hypogonadism. Men 5,204; 45 80 (serum testosterone, 100 300 ng/dL) prostate-specific antigen (PSA) < ng/mL transdermal median 3.19-year follow-up. Osteoporosis criterion entry. Surprisingly, occurred (91 [3.5%] 2,601) (64 [2.46%] 2,603). typical osteoporotic fractures, ankle rib (typically trauma and/or risky activities) led overall group. Divergent behavioral trajectories groups, likely engagement greater risk, accounted findings. risk substantiated studies. circulating free DNA (cfDNA), consistent senescence. Because cfDNA increases decreases response treatment, fragmentation pathogenesis. Luo al.18 subjects, subjects arthritis, TREX1 (a clearance enzyme), reflects severity (DAS28 score). increase cGAS fragment sensor) osteoarthritis. adjuvant-induced ultraviolet-induced rat models, initiated Intravenous intra-articular injection fragmented potentiated suppressed out (TREX1Cre) rats produced cfDNA, activated CD8+ T-cells, decreased Foxp3+-cells, severe arthritic symptoms. E2F1 activator (AP)-1 regulated senescence-associated (SASP). aging-related senescence contribute autoimmune activation. Frailty vulnerability stressors typically serious deterioration domains, unintentional loss, exhaustion, activity, slowness, weakness (Fried frailty phenotype). U.K. Biobank data, al.19 diagnosis undergo neuroimaging assessment 325 health-related measures. Analysis subject baseline 483,033; 46,501), 40,210) 9-year follow-up significantly unhealthy lifestyle, poor fitness, mental health, adverse sexes ages, measures mostly middle subjects. total white-matter hyperintensity gray-matter volume subcortical brain regions. large population-based valuable multimodal characterization Falls injury-related morbidity mortality United States. risks, economic burden, falls, U.S. Preventive Services Task Force updated evidence report20 comprising systematic meta-analysis fair-quality good-quality RCTs examine effectiveness multifactorial (28 RCTs; n 27,784) (37 16,117) falls community-dwelling (≥65 Multifactorial (individualized targeted based factors) individual ≥1 injurious fall-related fractures. Exercise (supervised setting components) Harms rare. concluded fall incidence, offers outcomes. Upcoming Meetings Events Related Orthopaedic Basic Science 2025 Annual Meeting Research Society (ORS) will held February 11, 2025, Phoenix, Arizona, OARSI World Congress Osteoarthritis April 24 27, Incheon, Korea. Gordon Conference Cartilage Biology Pathology: Genes, Molecules Mechanics Development March 23 28, Pomona, California, Stem Cell (ISSCR) June 14, Hong Kong. American Mineral (ASBMR) September 4 8, Seattle, Washington, 33rd European 19, Davos, Switzerland. 18th Regeneration & Joint Preservation (ICRS) October Boston, Massachusetts,

Язык: Английский

Процитировано

Trajectory-centric framework TrajAtlas reveals multi-scale differentiation heterogeneity among cells, genes, and gene modules in osteogenesis DOI

Litian Han, Yaoting Ji,

Yiqian Yu

и другие.

PLoS Genetics, Год журнала: 2024, Номер 20(10), С. e1011319 - e1011319

Опубликована: Окт. 22, 2024

Osteoblasts, the key cells responsible for bone formation and maintenance of skeletal integrity, originate from a diverse array progenitor cells. However, mechanisms underlying osteoblast differentiation these multiple osteoprogenitors remain poorly understood. To address this knowledge gap, we developed comprehensive framework to investigate at scales, encompassing cells, genes, gene modules. We constructed reference atlas focused on differentiation, which incorporates various provides seven-level cellular taxonomy. reconstruct process, model that identifies transcription factors pathways involved in different osteoprogenitors. Acknowledging covariates such as age tissue type can influence created an algorithm detect differentially expressed genes throughout process. Additionally, implemented methods identify conserved pseudotemporal modules across samples. Overall, our systematically addresses heterogeneity observed during sources, offering novel insights into complexities serving valuable resource understanding osteogenesis.

Язык: Английский

Процитировано

Surveying the landscape of emerging osteoanabolic therapies DOI

Thomas H. Ambrosi

Nature Reviews Endocrinology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Язык: Английский

Процитировано

Chromatin-site-specific accessibility: A microtopography-regulated door into the stem cell fate DOI

Wenyan Zhou,

Junxin Lin, Qianchun Wang

и другие.

Cell Reports, Год журнала: 2024, Номер 44(1), С. 115106 - 115106

Опубликована: Дек. 25, 2024

Язык: Английский

Процитировано

YAP regulates periosteal expansion in fracture repair DOI

Madhura P. Nijsure, Brendan Tobin, Dakota L. Jones

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 23, 2024

Bone fracture repair initiates by periosteal expansion. The periosteum is typically quiescent, but upon fracture, cells proliferate and contribute to bone repair. expansion of the regulated gene transcription; however, molecular mechanisms behind are unclear. Here, we show that Yes-Associated Protein (YAP) transcriptional coactivator with PDZ-binding motif (TAZ) mediate cell proliferation. increases number YAP-expressing cells, deletion YAP TAZ from Osterix (Osx) expressing impairs early Mechanistically, regulates both 'cell-intrinsic' 'cell-extrinsic' factors allow for Specifically, identified Morphogenetic 4 (BMP4) as a extrinsic factor YAP, rescues impairment YAP/TAZ deletion. Together, these data establish mediated induce in stages provide new putative targets therapeutic interventions.

Язык: Английский

Процитировано