What’s New in Musculoskeletal Basic Science

Musculoskeletal basic science research expands our knowledge on human health and disease and drives innovation and progress in clinical practice by enabling new means to effectively predict, prevent, diagnose, and treat orthopaedic conditions. The past year has been rich in exciting musculoskeletal discoveries, including in adult mammalian regeneration, diet-related infection susceptibility, and identifying new bone remodeling regulators with high therapeutic translation potential. In complex mechanistic studies, new epigenetic functions of vitamins C and D were established and our knowledge was enhanced by delineating factors and conditions predisposing to bone loss and fracture risk. Finally, new insight into cellular and/or molecular pathways was revealed for skeletal stem cell renewal and differentiation pertinent to bone healing, muscle regeneration, skeletal development, and growth. The vast number of excellent studies published last year demanded extremely rigorous review to select only groundbreaking articles. Although the selection was inherently subjective, it prioritized publications reporting novel studies that were highly relevant to orthopaedics. The main criteria were scientific quality, merit, and innovative methodology, with no preference regarding the specific musculoskeletal domains. All 20 musculoskeletal basic science articles that were selected for featuring in this Guest Editorial have been published in prestigious, high-impact-factor, multidisciplinary journals. The ample presence of musculoskeletal topics in these journals reflects the high quality and importance of current orthopaedic research in modern science. Adult Mammalian Regeneration Scarless restoration of injured adult skin is hampered by a limited understanding of mechanisms governing skin regeneration. Sinha et al.1 reported that full-thickness injuries (excision or burn) to reindeer (Rangifer tarandus) antler skin (velvet) regenerated with the restoration of hair follicles, pigmentation, and glands, indistinguishable from uninjured velvet. The same injuries to the back skin healed with hypertrophic fibrosis, contracture, and near-absent appendages, reminiscent of human scars. The transplantation of injured velvet fibroblasts to injured back skin yielded skin regeneration nearly equivalent to native velvet, indicating an intrinsic regeneration capacity of velvet cells. Uninjured velvet fibroblasts revealed an expression of regenerative genes (CRABP1, MDK, RUNX1, PRSS35, PTN), resembling human fetal fibroblasts, whereas back skin fibroblasts expressed inflammatory mediators (CXCL1, CXCL3, CCL2) mimicking profibrotic adult human fibroblasts. Although velvet fibroblasts activated genes implicated in cell plasticity, back skin cells stimulated proinflammatory networks (nuclear factor kappa B [NF-κB]1/2). The study indicated that decoupling fibroblast-immune system interactions may be a novel approach to mitigate skin scarring. Deer antlers undergo a remarkable cycle of shedding and regrowing, becoming larger and more complex every year. Qin et al.2 identified and characterized PRRX1+ mesenchymal stem cells (PMSCs) in a male sika deer (Cervus nippon) essential for antler regeneration. PMSCs were abundantly present in periosteal pedicles and comprised heterogeneous SFRP2+, PMF1+, and CXCL14+ subpopulations before antler casting and additional TNN+ cells 5 days after casting. The transplantation of TNN+ PMSCs to the skulls of nude mice generated antler-like structure containing cartilage and bone. TNN+ PMSCs were transcriptomically linked to the PMF1+ resting periosteal stem cells activated via the Wnt and TGF-β pathways. Species comparisons revealed TNN+ PMSC presence in the regenerable mouse fingertip, axolotl limb blastema, and murine growth plate. The study provides a spatiotemporal cellular atlas of deer antler regeneration with potential applicability to mammalian bone growth or repair. Fasting-Refeeding and Infection Susceptibility Caloric excess reduces lifespan and increases disease risk by impairing immunity and metabolism, whereas caloric restriction appears salutogenic. Janssen et al.3 researched the effects of fasting and refeeding on murine monocytes. Four-hour active fasting decreased Ly-6Chi monocytes circulating in blood, due to their migration to bone marrow, and was orchestrated by the hypothalamic-pituitary-adrenal axis, which stimulated corticosterone release, and by monocyte CXCR4 expression. Interestingly, refeeding prompted a vigorous surge of monocytes from the marrow into the bloodstream, causing monocytosis. Refeeding-generated circulating monocytes were chronologically older and transcriptionally distinct (ApoE, Chi3l3, Lpl), thereby altering immunity, increasing inflammation, and reducing the response to bacterial infection. The study demonstrated that temporal patterns of food intake modulate monocyte availability, lifespan, and function, which may be relevant for osteoclastogenesis. New Regulators of Bone Remodeling Pyroptosis, a form of lytic cell death, is due to the activation of caspase-1 in humans (caspase-11 in mice), which, at p30NT, cleaves Gasdermin D (GSDMD), a pore-forming molecule, thus causing cell rupture. Li et al.4 identified a new noninflammatory function of GSDMD in regulating osteoclasts. In the late stage of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, GSDMD cleaved with RIPK1 and caspase-8/3 yielded protein p20. In osteoclasts, GSDMD-p20 localized to an early endosome and, via binding to phosphatidylinositol 3-phosphate, restricted lysosomal maturation essential for osteoclasts to resorb bone. A similar role of GSDMD was apparent in aged or ovariectomy bone phenotypes. Gsdmd-deficient mice (Gsdmd−/− or Gsdmdfl/flLyz-Cre+) demonstrated osteoclasts with excessive lysosomal activity and large ruffled borders, causing bone erosions. Myeloid-specific Gsdmd deletion yielded an osteoporotic phenotype and high serum CTX-I levels, but unaffected osteoblastic bone formation. Lentiviral delivery of p20 rescued the Gsdmd−/− phenotype. The study identified GSDMD as a potent osteoclast activity regulator with potential therapeutic targeting. Osteoclasts are formed by the successive fusions of mononucleated monocytes and/or macrophages. Whitlock et al.5 revealed a new function of the La protein, which, apart from its known role as the nuclear RNA chaperone, regulated human and murine osteoclastogenesis. La was present in primary human monocytes, nearly disappeared in macrophage colony-stimulating factor (M-CSF)-treated precursors, and abundantly reappeared 3 days after RANKL stimulation. During robust fusion, La appeared on the osteoclast surface, and as fusion plateaued, it reappeared as phosphorylated, full-length La in the mature osteoclast nuclei; this transition acted as an off-switch for fusion. The La fusion activity involved direct interactions with Annexin A5, which anchored La to transiently exposed phosphatidylserine at the fusing osteoclast surfaces. Targeting surface La in explants from a fibrous dysplasia model (GαsR201C) revealed the characteristic excessive osteoclastogenesis. These findings indicate that La is a potent osteoclast fusion regulator with a potential for therapeutic targeting. Parathyroid hormone (PTH) is an essential calcium regulator secreted from parathyroid glands. PTH receptors were identified in the central neural system, suggesting a PTH role in neuronal signaling. Zhang et al.6 identified the subfornical organ, located near the third ventricle of the central neural system, which, in addition to body fluid homeostasis, also regulates serum PTH levels. Using retrograde tracing, the neuronal connection between the parathyroid glands and the central neural system nuclei was identified. The PTH entered and bound directly within the central neural system and activated neurons in the periventricular areas. Subfornical organ neurons expressed PTH-1 and PTH-2 receptors, with respective GABAergic and glutamatergic activity. Activation of the glutamatergic nerves led to elevated serum PTH and bone mass, whereas stimulation of GABAergic neurons exhibited the opposite effects. The periventricular neurons and peripheral sympathetic system were downstream of the subfornical organ in this feedback loop. This study revealed the central neural system regulation of serum PTH at the cellular and circuit levels and elucidates the uncontrollable serum PTH in late-stage hyperparathyroidism and its related neuropsychiatric symptoms. Energy metabolism during physical exercise infers the existence of communication between tissues and organs. Dong et al.7 assessed whether signals to initiate and sustain energy demands during physical exercise originate from bone. They previously showed that interleukin-11 (IL-11) is expressed in bone and is upregulated upon loading and, more recently, that IL-11 coupled physical exercise-induced bone remodeling with adipose metabolism. The deletion of the Il11 gene (Il11−/−) led to bone loss due to inhibition of Wnt signaling, causing reduced bone formation and unchanged bone resorption. IL-11-receptor-α (IL-11Rα) knock-out mice (Il11rα−/−) demonstrated that IL-11, via IL-11Rα, enhanced STAT1/3 phosphorylation, which downregulated Sost, with no effect on Rankl or Opg. Unloading (tail suspension) caused bone mineral density loss in both Il11−/− and wild-type (WT) mice, whereas the return to loading restored bone mineral density, but only in WT mice. The bone changes in Il11−/− mice were concurrent with marrow adiposity, increased systemic white adipose (visceral and subcutaneous), and high leptin and low adiponectin, leading to insulin resistance and glucose intolerance. Il11 deletion in osteoblasts (Ocn-Cre;Il11fl/fl) recapitulated bone loss and increased adiposity, whereas adiponectin-driven Cre in Il11−/− mice (Apn-Cre;Il11fl/fl) had no such effects, indicating that osteoblasts and/or osteocytes are the major source of IL-11, whereas adipocytes respond to it via IL-11Rα. The study delineates the physiological role of osteoblast and/or osteocyte-derived IL-11 in bone remodeling and response to loading with the involvement of body adipose and offers new insight into pathomechanisms of bone deterioration in dyslipidemia. Conditions Involving Bone Loss and Fracture Risk Long-term data on bone health in childhood cancer survivors, to guide osteoprotective measures, have been lacking. Van Atteveld et al.8 performed a cross-sectional study using the Dutch Childhood Cancer Survivor Study (DCCSS) LATER, which included patients with a malignancy before 19 years of age and surviving ≥5 years. Of 1,548 participants assessed with dual x-ray absorptiometry, 36.1% had low bone mineral density (Z-score ≤ −1) and 9.6% had very low bone mineral density (Z-score ≤ −2). The standardized incidence ratio of any first fracture was 3.53 (95% confidence interval [CI], 3.06 to 4.06) for male patients and 5.35 (95% CI, 4.46 to 6.52) for female patients, and vertebral fractures occurred in 13.3% participants. Male sex, underweight, treatment with platinum compounds, radiation therapy, hypogonadism, hyperthyroidism, low physical activity, smoking, and vitamin D deficiency were associated with low or very low bone mineral density. The study demonstrated that childhood cancer survivors are vulnerable to bone loss and fracture risk and may require surveillance and prophylaxis. Physical activity can retard bone loss, although its greatest anabolic bone effects occur before menopause, indicating that a woman’s hormonal status controls these benefits. Greendale et al.9 assessed the effects of exercise on bone during the menopause transition. Data from the Study of Women’s Health Across the Nation (SWAN), which comprises a longitudinal, repeated-measure, long-term cohort of U.S. women, were analyzed for the menopause transition, bone mineral density, and leisure time physical activity. In the study by Greendale et al., 875 women experiencing natural menopause were analyzed. The menopause transition was separated into premenopause-early perimenopause (Period 1) and late perimenopause-postmenopause (Period 2). Hip or spine bone mineral density was measured at least once for each period, and leisure time physical activities were assessed using a validated Kaiser Physical Activity Survey (KPAS) at baseline and 7 visits. The study demonstrated that greater leisure time physical activity (walking, calisthenics, swimming, bicycling, yoga) during the menopause transition directly related to better hip and spine bone mineral densities. Even modest leisure time physical activity was beneficial for reducing bone mineral density loss. The theoretical leisure time physical activity advantage calculated to slow bone mineral density loss would relate to a 7.8% relative lower fracture risk. The study is a unique attempt to assess physical activity metrics and to relate them to bone health for women in perimenopause. Patients with inflammatory bowel diseases, mainly ulcerative colitis and Crohn’s disease, exhibit bone loss and fracture risk due to immunosuppressive treatment, malabsorption, and systemic inflammation. Using established ulcerative colitis and Crohn’s disease mouse models, Guo et al.10 investigated bone-marrow-derived stem cells (BMSCs) and tested the delivery of Wnt agonist 1 to BMSCs via Golgi glycoprotein 1 exosome-nanoparticles (GLG1-NPs), to mitigate inflammatory bowel disease-induced bone loss. Both ulcerative colitis and Crohn’s disease models demonstrated a considerably compromised bone phenotype, upregulation of inflammatory cytokines, and suppression of the osteogenic Wnt/β-catenin pathway. Human BMSCs cultured in serum from patients with ulcerative colitis revealed markedly decreased osteoblastic gene expression (OCN, OSX, RUNX2) and upregulation of adipogenic genes (FABP4, PPARG). The delivery of GLG1-NPs with the Wnt agonist rescued the bone phenotype in mice with ulcerative colitis and augmented the healing of a femoral osteotomy. The study highlighted the critical role of the inflammatory microenvironment in inflammatory bowel disease-related bone loss and proposed GLGF1-NPs as an anabolic therapy. Chronic glucocorticoids lead to osteoporosis, fracture risk, and marrow adiposity. Liu et al.11 mechanistically studied bone marrow adipocytes (BMAs) in adult mice treated with methylprednisolone. They developed a p16tdTom senescence reporter mouse and demonstrated that methylprednisolone rapidly initiated cellular senescence in lineage-committed BMAs, which acquired the senescence-associated secretory phenotype (SASP). Senescent cells accumulated in a time-dependent methylprednisolone exposure: early (<2 weeks), solely involving senescent adipocytes (perilipin+), and later (>4 weeks), also involving other senescent cells (endothelium, osteoblasts, and stem cells). BMA-initiated senescence permeated to other cell types via SASP. Methylprednisolone increased the synthesis of oxylipins (15d-PGJ2), which stimulated senescence and further promoted oxylipins in BMAs, a positive feedback loop. The transplantation of senescent BMAs to healthy mice triggered the spread of senescence to bone and marrow and produced bone loss, whereas using the SASP inhibitor (JAKi) rescued the bone phenotype in methylprednisolone-treated mice. The study elucidated the chronic glucocorticoid effects on bone and suggested potential therapeutic countermeasures. Hip fractures lack well-characterized genetic and clinical determinants as causal risk factors. Nethander et al.12 embarked on a genome-wide association study and a Mendelian randomization study to establish the genetic determinants of the risk of hip fracture. Data from 5 large, northern European biobanks (11,516 hip fractures; 723,838 controls) were used to perform a large-scale, genome-wide association study meta-analysis. An examination of 9,457,767 variants revealed 5 genomic loci associated with the risk of hip fracture. The non-bone mineral density-related signal (APOE locus on 19q13.32) was linked to Alzheimer disease and fall risk, whereas the other 4 loci (REST on 4q12, HOXC8 on 12q13.13, SALL1 on 16q12.1, and ETS2 on 21q22.2) were associated with decreased bone mineral density. Mendelian randomization analysis showed a strong causal role of low femoral-neck bone mineral density (odds ratio [OR], 2.25 [95% CI, 1.91 to 2.65]) and identified only Alzheimer disease (OR, 1.08 [95% CI, 1.06 to 1.11]) and having ever smoked regularly (OR, 1.06 [95% CI, 1.00 to 1.12]) as exhibiting a moderate causal association with hip fracture. The study comprised the most comprehensive assessment of the genetic determinants of the risk of hip fracture to date. Factors Affecting Bone Healing Chronic mental stress is associated with growth retardation, osteoporosis, and fracture risk. Tschaffon-Müller et al.13 analyzed the effect of mental stress on bone healing clinically and in mice. In patients with ankle fracture, depression, psychosocial stress, and low social functioning were associated with an increased expression of tyrosine hydroxylase (TH) in fracture hematoma and delayed bone healing. In chronic subordinate colony housing (CSC) mice (a model of depression), the healing of a femoral osteotomy was delayed and exhibited a selective increase in TH+Ly6G+ neutrophils in hematoma. TH-deficient myeloid cells (THfloxCre+) protected CSC mice against negative stress effects on bone healing and growth retardation, whereas fracture callus in THflox/Cre− CSC mice revealed decreased Runx2+ hypertrophic chondrocytes and increased osteoclasts. Propranolol use prior to fracture surgery reduced TH+ neutrophils in hematoma and improved bone healing in CSC mice. Knocking-out of the β2-adrenergic receptor (Adrb2floxCre+) in chondrocytes of CSC mice protected against negative stress effects on bone healing. The study reveals that neutrophil-derived catecholamines compromise endochondral ossification and supports short-term β-blocker use to mitigate the effects of chronic mental stress on bone healing. High-resolution light-sheet imaging offered a unique opportunity to visualize lymphatic circulation in bone. Biswas et al.14 developed a rapid, single-cell-resolution quantitative panoptic 3-dimensional (3D) imaging and demonstrated the presence of lymphatic vessels in mouse and human bones and established their unique role in bone and hematopoietic regeneration. Lymphatic vessels in bone expanded during genotoxic stress caused by radiation or chemotherapy followed by the transplantation of marrow cells. This dramatic expansion of lymphatic vessels was ablated with SAR131675, which acts on vascular endothelial growth factor (VEGF) receptor 3. The VEGF-C/VEGFR-3 signaling and genotoxic-stress-induced IL-6 drove lymphangiogenesis in bones, and CXCL12 secreted from lymphatic endothelial cells triggered expansion of mature Myh11+CXCR4+ pericytes, which contributed to bone and hematopoietic regeneration. In aged animals, the expansion of lymphatic vessels and Myh11+ cells in response to genotoxic stress was impaired. These data suggested lymphangiogenesis as a potential therapeutic option to stimulate bone healing. Although male and female sex hormones have known effects on bone, the mechanisms driving their dimorphic roles in bone healing are less clear. Andrew et al.15 mechanistically explored sex hormone effects on fracture healing in young adult male mice, sham-operated competent-ovary female mice, and ovariectomized (OVX) mice. At 2 weeks after the fracture, male mice exhibited the highest callus volume and strength, whereas the OVX mice exhibited the lowest callus volume and strength. The intact femora of sham mice compared with OVX mice revealed no difference in skeletal stem cells (SSCs) and bone stromal progenitors (BSPs); however, SSCs and BSPs were significantly reduced in the OVX fractured femora, and the osteogenic differentiation of SSCs and BSPs was inferior. SSCs in male intact and fractured femora were significantly higher than in their female counterparts. Supplementation of OVX mice with 17-β-estradiol increased skeletal bone mass, rescued fracture callus, increased the activity of SSCs, and restored the expression of osteogenic genes coexpressed with an estrogen receptor. The same 17-β-estradiol delivery to male mice had no effect on fracture healing. Similar results were obtained for in vitro and in vivo functional assays of human male and female SSCs isolated from the femoral head or fracture callus. The study delineated sexually dimorphic responsiveness of human and murine SSCs to estrogens and suggested estrogen supplementation for estrogen-deficient women during bone healing. New Epigenetic Functions of Vitamins Humans (as well as bats and guinea pigs) lost the ability to endogenously synthesize vitamin C due to mutations in the L-gulono-γ-lactone oxidase gene (GULOP) and now rely on dietary vitamin C. Although vitamin C plays an established role in collagen synthesis, research has suggested that vitamin C may elicit an additional osteogenic function. In a mechanistic study, Thaler et al.16 demonstrated that vitamin C exhibited robust epigenetic functions to orchestrate osteogenesis by creating a transcriptionally permissive state for the selective expression of all major bone genes. Gulo knock-out mice (Gulo−/−), dependent on exogenous vitamin C, were allowed to mature with vitamin C in food and then vitamin C was withdrawn. Vitamin C-deficient mice exhibited a compromised bone phenotype compared with vitamin C-supplemented Gulo−/− or WT mice. The chromatin accessibility gatekeepers, H3K9me3 and H3K27me3, as well as the transcriptional activation mark 5hmC on DNA, revealed apparent changes in bone, the liver, and the heart. Vitamin C-deficient mouse bones exhibited the most prominent 5hmC reduction, indicating that DNA hydroxymethylation was particularly vitamin C-sensitive and correlated with downregulation of bone-selective genes (Bglap, Dkk1, Dmp1). Vitamin C stimulated the activity of DNA-cytosine dioxygenases and histone 3 demethylases (H3K9me3, H3K27me3). The resulting epigenetic landscape consisted of activating 5hmC modification and de-repressed H3K9/H3K27 histone marks. Bone cells during all stages of osteogenic differentiation required vitamin C, whereas vitamin C appeared dispensable for adipogenesis. The study revealed vitamin C to epigenetically coordinate osteogenic differentiation before it exerts effects on collagen deposition and/or maturation. Embryonic vitamin D deficiency increases the risks of obesity, insulin resistance, and type-2 diabetes, despite adequate post-birth vitamin D supplementation. Oh et al.17 demonstrated that the transplantation of fetal hematopoietic stem cells (HSCs) obtained from vitamin D-deficient mouse embryos to vitamin D-sufficient mice induced type-2 diabetes and identified an epigenetic program that induced type-2 diabetes postnatally. Female mice were fed with a vitamin D-deficient or vitamin D-sufficient food for 4 weeks before pregnancy. Vitamin D-sufficient mice, as recipients of vitamin D-deficient HSCs, demonstrated a pattern of immune cell progenitors similar to donor vitamin D-deficient HSCs, with more long-term and short-term HSCs and myeloid progenitors compared with vitamin D-sufficient mice. Fetal vitamin D deficiency epigenetically repressed Jarid2 and activated the Mef2/PGC1α pathway in the HSCs, which persisted in the recipient bone marrow, causing adipose macrophage infiltration. The adipose macrophages secreted miR106-5p, which resulted in adipose insulin resistance. Recipients of vitamin D-deficient miR-106−/− HSCs had improved glucose tolerance and insulin sensitivity compared with vitamin D-deficient miR-106+/+ HSC recipients. Next, the clinical part of the study involving 30 healthy pregnant women and their full-term infants showed that two-thirds of newborns were vitamin D-deficient (25[OH]D ≤ 20 ng/mL), and cord-blood vitamin D levels directly correlated with newborn birth weight. Further, monocytes from vitamin D-deficient human cord blood exhibited comparable Jarid2/Mef2/PGC1α expression changes and miR-106b-5p secretion, causing adipose insulin resistance. These findings established that vitamin D is directly involved in embryonic epigenetic immune cell programing, and gestational vitamin D deficiency strongly predisposes a baby to insulin resistance and type-2 diabetes later in life. Muscle Physiology and Regeneration Muscle spindles comprise intrafusal fibers sensing muscle length alterations and relay these proprioceptive signals to the brain to coordinate movement, posture, and positional awareness. Cao et al.18 studied the role of low-density lipoprotein receptor-related protein 4 (LRP4) in muscle spindle embryonic and postnatal development and aging. The authors created Lrp4-CreERT2 mice with Ai9 reporter to label cells with an active LRP4 promoter. These mice formed the neuromuscular junction and displayed normal survival. Staining for annulospiral endings indicated that LRP4 was (fivefold more) highly expressed in muscle spindles. Lrp4−/− mice at E18.4 demonstrated a role of LRP4 in muscle spindle development. Inducible Lrp4 knockout in adult mice caused the loss of annulospiral endings, disrupted sensory synapses, and compromised movement coordination, indicating that LRP4 is needed for muscle spindle maintenance. In aged mice, muscle spindle sensory endings and function were impaired and could be alleviated by LRP4 expression. The study reveals a new function of LRP4 in muscle spindle formation and maintenance in adult and aged animals, thereby elucidating the etiology of diseases with altered proprioception. Fibro-adipogenic progenitors (FAPs) support satellite cells, thereby allowing muscle growth and remodeling in response to exercise or injury. FAPs exhibit transcriptomic heterogeneity, raising questions about their origin. Sastourné-Arrey et al.19 reported that FAP-like cells resided in subcutaneous adipose tissue (SAT) and, as adipose stromal cells (ASCs), were rapidly released in response to a muscle injury. After a muscle injury, FAPs expressed podoplanin and exhibited the transcriptome of ASCs (Sca-1+/CD34+/CD90+/podoplanin+/CD31−/CD45−), suggesting their SAT origin. Blood factors released after a murine muscle injury or human exercise triggered ASC egress from SAT and rapid trafficking to the muscle immediately after the injury, and this infiltration involved platelets, thus contributing to the FAP heterogeneity. Both inducing platelet depletion and podoplanin inhibition effectively reduced FAPs in the muscle, whereas the intramuscular delivery of ASCs rescued the process. Blocking infiltration of ASCs or removing SAT led to impaired muscle regeneration, indicating that SAT is an essential source of ASCs in the process. Periosteal Stem Cells Control the Growth Plate Bone harbors distinct, site-specific stem cells, which, in select regions, colocalize, thus implying potential interactions. Tsukasaki et al.20 interrogated crosstalk between periosteal stem cells (PSCs), which distinctively contribute to intramembranous osteogenesis, and growth-plate resting-zone stem cells (RZSCs), which distinctively contribute to endochondral osteogenesis. The authors developed transgenic mice with cathepsin K (Ctsk)-Cre-mediated deletion of Prmt5 (Prmt5flox/ΔCtsk-Cre), in which Cre is expressed in PSCs. PRMT5, an enzyme for arginine demethylation, was characteristic for stem cells, whereas Ctsk-Cre was expressed in PSCs. Interestingly, Prmt5flox/ΔCtsk-Cre mice displayed impaired endochondral and intramembranous osteogenesis. Tracing Ctsk-Cre PSCs revealed that Prmt5 expression and Prmt5 levels decreased in PSCs, but not in growth plate chondrocytes, indicating that PSCs are selectively abrogated by Prmt5 deficiency. The ablation of PSCs caused progressive defects in intramembranous and endochondral osteogenesis due to a PSC-derived Indian hedgehog deficiency. These findings demonstrated that periosteal and growth plate cells engage in an Indian hedgehog-dependent crosstalk during bone developmental and postnatal growth. Upcoming Meetings and Events Related to Orthopaedic Basic Science The 2024 Annual Meeting of the Orthopaedic Research Society (ORS) will be held from February 2 to 6, 2024, in Long Beach, California. The 2024 Osteoarthritis Research Society International (OARSI) World Congress on Osteoarthritis will be held on April 18 to 21, 2024, in Vienna, Austria. The Gordon Research Conference, Bones and Teeth: Advances in Mineralized Tissue Development, Disease, and Regeneration will be held from January 28 to February 2, 2024, in Galveston, Texas. The International Society for Stem Cell Research (ISSCR) 2024 Annual Meeting will be held from July 10 to 13, 2024, in Hamburg, Germany. The 7th International Cartilage Regeneration & Joint Preservation Society (ICRS) Summit: From Molecule to Metal: How to Get It Right? Driving Personalized Knee Preservation Forward will be held from September 25 to 27, 2024, in Italy. The 32nd Annual Meeting of the European Orthopaedic Research Society (EORS) will be held from September 18 to 20, 2024, in Aalborg, Denmark. The American Society for Bone and Mineral Research (ASBMR) 2024 Annual Meeting will be held from September 27 to 30, 2024, in Toronto, Ontario, Canada.