Skeletal Stem Cells: A Basis for Orthopaedic Pathology and Tissue Repair.

➢ Skeletal stem cells (SSCs) continually replenish mature cell populations to support skeletal homeostasis.➢ SSCs repopulate by self-renewal, have multilineage potential, and are long-lived in vivo.➢ SSCs express specific combinations of cell surface markers that reflect their lineage identity.

Schnurri-3 inhibition rescues skeletal fragility and vascular skeletal stem cell niche pathology in the OIM model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a disorder of low bone mass and increased fracture risk due to a range of genetic variants that prominently include mutations in genes encoding type I collagen. While it is well known that OI reflects defects in the activity of bone-forming osteoblasts, it is currently unclear whether OI also reflects defects in the many other cell types comprising bone, including defects in skeletal vascular endothelium or the skeletal stem cell populations that give rise to osteoblasts and whether correcting these broader defects could have therapeutic utility. Here, we find that numbers of skeletal stem cells (SSCs) and skeletal arterial endothelial cells (AECs) are augmented in Col1a2 mice, a well-studied animal model of moderate to severe OI, suggesting that disruption of a vascular SSC niche is a feature of OI pathogenesis.

Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion.

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3 (Shn3) mice with augmented osteoblast activity, we show Shn3mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3mice, indicating this phenotype is driven by skeleton.

Prevention and treatment of peri-implant fibrosis by functionally inhibiting skeletal cells expressing the leptin receptor.

The cellular and molecular mediators of peri-implant fibrosis-a most common reason for implant failure and for surgical revision after the replacement of a prosthetic joint-remain unclear. Here we show that peri-implant fibrotic tissue in mice and humans is largely composed of a specific population of skeletal cells expressing the leptin receptor (LEPR) and that these cells are necessary and sufficient to generate and maintain peri-implant fibrotic tissue. In a mouse model of tibial implantation and osseointegration that mimics partial knee arthroplasty, genetic ablation of LEPR cells prevented peri-implant fibrosis and the implantation of LEPR cells from peri-implant fibrotic tissue was sufficient to induce fibrosis in secondary hosts.

Are osteoblasts multiple cell types? A new diversity in skeletal stem cells and their derivatives.

Only in the past decade have skeletal stem cells (SSCs), a cell type displaying formal evidence of stemness and serving as the ultimate origin of mature skeletal cell types such as osteoblasts, been defined. Here, we discuss a pair of recent reports that identify that SSCs do not represent a single cell type, but rather a family of related cells that each have characteristic anatomic locations and distinct functions tailored to the physiology of those sites. The distinct functional properties of these SSCs in turn provide a basis for the diseases of their respective locations.

A translational murine model of aseptic loosening with osseointegration failure.

An in vivo animal model of a weight-bearing intra-articular implant is crucial to the study of implant osseointegration and aseptic loosening caused by osseointegration failure. Osseointegration, defined as a direct structural and functional attachment between living bone tissue and the surface of a load-carrying implant, is essential for implant stability and considered a prerequisite for the long-term clinical success of implants in total joint arthroplasty. Compared to large animal models, murine models offer extensive genetic tools for tracing cell differentiation and proliferation.

Differential Gene Expression Involved in Bone Turnover of Mice Expressing Constitutively Active TGFβ Receptor Type I.

Transforming growth factor beta (TGF-β) is ubiquitously found in bone and plays a key role in bone turnover. Mice expressing constitutively active TGF-β receptor type I ( mice) are osteopenic. Here, we identified the candidate genes involved in bone turnover in mice using RNA sequencing analysis.

Advances in Bone-Targeting Drug Delivery: Emerging Strategies Using Adeno-Associated Virus.

The development of bone-targeting drug delivery systems holds immense promise for improving the treatment of skeletal diseases. By precisely delivering therapeutic agents to the affected areas of bone, these strategies can enhance drug efficacy, minimize off-target effects, and promote patient adherence, ultimately leading to improved treatment outcomes and an enhanced quality of life for patients. This review aims to provide an overview of the current state of affinity-based bone-targeting agents and recent breakthroughs in innovative bone-targeting adeno-associated virus (AAV) strategies to treat skeletal diseases in mice.

Development of AAV-Mediated Gene Therapy Approaches to Treat Skeletal Diseases.

Adeno-associated viral (AAV) vectors have emerged as crucial tools in advancing gene therapy for skeletal diseases, offering the potential for sustained expression with low postinfection immunogenicity and pathogenicity. Preclinical studies support both the therapeutic efficacy and safety of these vectors, illustrating the promise of AAV-mediated gene therapy. Emerging technologies and innovations in AAV-mediated gene therapy strategies, such as gene addition, gene replacement, gene silencing, and gene editing, offer new approaches to clinical application.

The performance of artificial intelligence chatbot large language models to address skeletal biology and bone health queries.

Artificial intelligence (AI) chatbots utilizing large language models (LLMs) have recently garnered significant interest due to their ability to generate humanlike responses to user inquiries in an interactive dialog format. While these models are being increasingly utilized to obtain medical information by patients, scientific and medical providers, and trainees to address biomedical questions, their performance may vary from field to field. The opportunities and risks these chatbots pose to the widespread understanding of skeletal health and science are unknown.

Skeletal stem cells in bone development, homeostasis, and disease.

Tissue-resident stem cells are essential for development and repair, and in the skeleton, this function is fulfilled by recently identified skeletal stem cells (SSCs). However, recent work has identified that SSCs are not monolithic, with long bones, craniofacial sites, and the spine being formed by distinct stem cells. Recent studies have utilized techniques such as fluorescence-activated cell sorting, lineage tracing, and single-cell sequencing to investigate the involvement of SSCs in bone development, homeostasis, and disease.

Characterization of the Nucleus Pulposus Progenitor Cells via Spatial Transcriptomics.

Loss of refreshment in nucleus pulposus (NP) cellularity leads to intervertebral disc (IVD) degeneration. Nevertheless, the cellular sequence of NP cell differentiation remains unclear, although an increasing body of literature has identified markers of NP progenitor cells (NPPCs). Notably, due to their fragility, the physical enrichment of NP-derived cells has limited conventional transcriptomic approaches in multiple studies.

Capacity for large language model chatbots to aid in orthopedic management, research, and patient queries.

Large language model (LLM) chatbots possess a remarkable capacity to synthesize complex information into concise, digestible summaries across a wide range of orthopedic subject matter. As LLM chatbots become widely available they will serve as a powerful, accessible resource that patients, clinicians, and researchers may reference to obtain information about orthopedic science and clinical management. Here, we examined the performance of three well-known and easily accessible chatbots-ChatGPT, Bard, and Bing AI-in responding to inquiries relating to clinical management and orthopedic concepts.

Distinct mesenchymal cell states mediate prostate cancer progression.

In the complex tumor microenvironment (TME), mesenchymal cells are key players, yet their specific roles in prostate cancer (PCa) progression remain to be fully deciphered. This study employs single-cell RNA sequencing to delineate molecular changes in tumor stroma that influence PCa progression and metastasis. Analyzing mesenchymal cells from four genetically engineered mouse models (GEMMs) and correlating these findings with human tumors, we identify eight stromal cell populations with distinct transcriptional identities consistent across both species.

Lipopolysaccharide Impedes Bone Repair in -Deficient Mice.

Chronic inflammation contributes to the development of skeletal disorders in patients with systemic lupus erythematosus (SLE). Activation of the host immune response stimulates osteoclast activity, which in turn leads to bone loss. Regenerating bone in the inflammatory microenvironments of SLE patients with critical bone defects remains a great challenge.

Sfrp4 is required to maintain Ctsk-lineage periosteal stem cell niche function.

We have previously reported that the cortical bone thinning seen in mice lacking the Wnt signaling antagonist is due in part to impaired periosteal apposition. The periosteum contains cells which function as a reservoir of stem cells and contribute to cortical bone expansion, homeostasis, and repair. However, the local or paracrine factors that govern stem cells within the periosteal niche remain elusive.

Inducing Angiogenesis in the Nucleus Pulposus.

Bone morphogenetic protein (BMP) gene delivery to Lewis rat lumbar intervertebral discs (IVDs) drives bone formation anterior and external to the IVD, suggesting the IVD is inhospitable to osteogenesis. This study was designed to determine if IVD destruction with a proteoglycanase, and/or generating an IVD blood supply by gene delivery of an angiogenic growth factor, could render the IVD permissive to intra-discal BMP-driven osteogenesis and fusion. Surgical intra-discal delivery of naïve or gene-programmed cells (BMP2/BMP7 co-expressing or VEGF expressing) +/- purified chondroitinase-ABC (chABC) in all permutations was performed between lumbar 4/5 and L5/6 vertebrae, and radiographic, histology, and biomechanics endpoints were collected.

A multi-stem cell basis for craniosynostosis and calvarial mineralization.

Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC (CTSK CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2 CSC) that we identified in this study.

A vertebral skeletal stem cell lineage driving metastasis.

Vertebral bone is subject to a distinct set of disease processes from long bones, including a much higher rate of solid tumour metastases. The basis for this distinct biology of vertebral bone has so far remained unknown. Here we identify a vertebral skeletal stem cell (vSSC) that co-expresses ZIC1 and PAX1 together with additional cell surface markers.

AI Chatbots in Clinical Laboratory Medicine: Foundations and Trends.

Background: Artificial intelligence (AI) conversational agents, or chatbots, are computer programs designed to simulate human conversations using natural language processing. They offer diverse functions and applications across an expanding range of healthcare domains. However, their roles in laboratory medicine remain unclear, as their accuracy, repeatability, and ability to interpret complex laboratory data have yet to be rigorously evaluated.

Accelerated Bone Loss in Transgenic Mice Expressing Constitutively Active TGF-β Receptor Type I.

Transforming growth factor beta (TGF-β) is a key factor mediating the intercellular crosstalk between the hematopoietic stem cells and their microenvironment. Here, we investigated the skeletal phenotype of transgenic mice expressing constitutively active TGF-β receptor type I under the control of Mx1-Cre ( mice). μCT analysis showed decreased cortical thickness, and cancellous bone volume in both femurs and mandibles.

Gene Therapy to Treat Osteopenia Associated With Chronic Ethanol Consumption and Aldehyde Dehydrogenase 2 Deficiency.

Aldehyde dehydrogenase 2 (ALDH2) deficiency affects 35% to 45% of East Asians and 8% of the world population. ALDH2 is the second enzyme in the ethanol metabolism pathway. The common genetic variant allele has a glutamic acid-to-lysine substitution at position 487 (E487K) that reduces the enzyme activity, resulting in an accumulation of acetaldehyde after ethanol consumption.