A NOTCH2 pathogenic variant and HES1 regulate osteoclastogenesis in induced pluripotent stem cells.

Hajdu Cheney Syndrome (HCS), a monogenic disorder associated with NOTCH2 pathogenic variants, presents with neurological, craniofacial and skeletal abnormalities. Mouse models of the disease exhibit osteopenia. To determine the consequences of a HCS pathogenic variant in human cells, induced pluripotent NCRM1 and NCRM5 stem (iPS) cells harboring a NOTCH2 mutation or null for HES1 alleles were created.

TNFα has differential effects on the transcriptome profile of selected populations in murine cartilage.

Objective: To further our understanding of the role of tumor necrosis factor (TNF)α on the inflammatory response in chondrocytes.

Design: We explored the effects of TNFα on the transcriptome of epiphyseal chondrocytes from newborn C57BL/6 mice at the total and single cell (sc) resolution.

Results: Gene set enrichment analysis of total RNA-Seq from TNFα-treated chondrocytes revealed enhanced response to biotic stimulus, defense and immune response and cytokine signaling and suppressed cartilage and skeletal morphogenesis and development.

New insights into the vitamin D/PTH axis in endocrine-driven metabolic bone diseases.

Background: Endocrine regulation of bone metabolisms is the focus of the "Skeletal Endocrinology" series of meetings.

Aims: To report on the outcome of the discussion on the role of vitamin D/PTH axis in endocrine osteopathies held during the 10 Skeletal Endocrinology Meeting which took place in Stresa (Italy) in March 2023.

Outcomes: Vitamin D/PTH axis has relevant influence on several outcomes in the general population and in patients affected by endocrinopathies such as hypoparathyroidism and secreting pituitary adenomas.

Sequential Depth Stimulation Within the Psoas Offers No Benefit for Localization of the Lumbar Plexus During Lateral Lumbar Fusion Surgery.

Study Design: Prospective cohort study.

Objectives: In this study we aim to assess the difference in triggered EMG readings throughout different depths in the psoas muscle during the lateral approach to the lumbar spine and their effect on surgeon decision making.

Methods: Three surgeons, practicing at different institutions, assessed triggered EMG readings during the trans psoas approach at the level of the disc and 5,10 and 15 millimeters into the psoas muscle with sequential dilators.

NOTCH2 promotes osteoclast maturation and metabolism and modulates the transcriptome profile during osteoclastogenesis.

Notch signaling plays a key regulatory role in bone remodeling and NOTCH2 enhances osteoclastogenesis, an effect that is mostly mediated by its target gene Hes1. In the present study, we explored mechanisms responsible for the enhanced osteoclastogenesis in bone marrow-derived macrophages (BMM) from Notch2, harboring a NOTCH2 gain-of-function mutation, and control mice. Notch2 mice are osteopenic and have enhanced osteoclastogenesis.

NOTCH2 sensitizes the chondrocyte to the inflammatory response of tumor necrosis factor α.

Notch regulates the immune and inflammatory response and has been associated with the pathogenesis of osteoarthritis in humans and preclinical models of the disease. Notch2 mice harbor a NOTCH2 gain-of-function and are sensitized to osteoarthritis, but the mechanisms have not been explored. We examined the effects of tumor necrosis factor α (TNFα) in chondrocytes from Notch2 mice and found that NOTCH2 enhanced the effect of TNFα on Il6 and Il1b expression.

Traumatic Sternoclavicular Dislocations in Athletes: Diagnosis, Indications for Surgical Reconstruction, and Guide for Return to Play.

Injuries to the sternoclavicular (SC) joint are rare, however, when they occur prompt recognition, evaluation, and treatment are crucial. SC joint injuries can occur following high-energy mechanisms such as motor vehicle collisions and contact sports. Injury to the SC joint can be evaluated with the use of plain radiographs as well as computed tomography.

Dual- Versus Single-Plate Fixation of Clavicle Fractures: Understanding the Rationale Behind both Approaches.

Clavicle fractures are a common injury resulting from a high-energy force, such as a fall onto the shoulder, motor vehicle accident, or sporting activity. Although some clavicle fractures may be treated nonoperatively, operative treatment results in higher union rates and faster return to activity. Here we discuss the operative treatment options for plating of clavicle fractures; specifically, a single plate placed either superiorly or anteriorly or two plates placed orthogonally.

Antisense oligonucleotides targeting a NOTCH3 mutation in male mice ameliorate the cortical osteopenia of lateral meningocele syndrome.

Lateral Meningocele Syndrome (LMS) is a monogenic disorder associated with NOTCH3 pathogenic variants that result in the stabilization of NOTCH3 and a gain-of-function. A mouse model (Notch3) harboring a 6691-TAATGA mutation in the Notch3 locus that results in a functional outcome analogous to LMS exhibits cancellous and cortical bone osteopenia. We tested Notch3 antisense oligonucleotides (ASOs) specific to the Notch3 mutation for their effects on Notch3 downregulation and on the osteopenia of Notch3 mice.

Clinical outcomes of posterior tibial tendon sheath ultrasound-guided corticosteroid injections.

Objectives: The purpose of this study was to assess the safety of ultrasound-guided corticosteroid injections into the posterior tibial tendon sheath for posterior tibialis tendinopathy. Secondary outcomes include duration of pain relief, amount of pain relief, need for repeat injections and progression to surgery.

Methods: We retrospectively reviewed all patients in our electronic medical record who underwent a posterior tibial tendon sheath (PTTS) steroid injection between 2015 and 2020 for the diagnosis of posterior tibial tendon dysfunction and/or posterior tibialis tendon insufficiency, and/or ankle pain.

Induced pluripotent stem cell technology in bone biology.

Technologies on the development and differentiation of human induced pluripotent stem cells (hiPSCs) are rapidly improving, and have been applied to create cell types relevant to the bone field. Differentiation protocols to form bona fide bone-forming cells from iPSCs are available, and can be used to probe details of differentiation and function in depth. When applied to iPSCs bearing disease-causing mutations, the pathogenetic mechanisms of diseases of the skeleton can be elucidated, along with the development of novel therapeutics.

Bilateral Flexor Digitorum Accessorius Longus Precipitating Bilateral Tarsal Tunnel Syndrome: A Case Report.

Case: A 29-year-old woman presented with bilateral tarsal tunnel syndrome caused by bilateral flexor digitorum accessorius longus, experiencing immediate relief of symptoms after surgical intervention through 1 year.

Conclusion: Accessory muscles can cause compressive neuropathies in multiple areas of the body. In patients who have FDAL as the cause of their tarsal tunnel syndrome, surgeons should have a high index of suspicion of bilateral FDAL if the same patient develops similar contralateral symptoms.

The Prone Lateral Approach for Lumbar Fusion-A Review of the Literature and Case Series.

Lateral lumbar interbody fusion is an evolving procedure in spine surgery allowing for the placement of large interbody devices to achieve indirect decompression of segmental stenosis, deformity correction and high fusion rates through a minimally invasive approach. Traditionally, this technique has been performed in the lateral decubitus position. Many surgeons have adopted simultaneous posterior instrumentation in the lateral position to avoid patient repositioning; however, this technique presents several challenges and limitations.

Wnt-associated adult stem cell marker Lgr6 is required for osteogenesis and fracture healing.

Despite the remarkable regenerative capacity of skeletal tissues, nonunion of bone and failure of fractures to heal properly presents a significant clinical concern. Stem and progenitor cells are present in bone and become activated following injury; thus, elucidating mechanisms that promote adult stem cell-mediated healing is important. Wnt-associated adult stem marker Lgr6 is implicated in the regeneration of tissues with well-defined stem cell niches in stem cell-reliant organs.

Induction of a NOTCH3 Lehman syndrome mutation in osteocytes causes osteopenia in male C57BL/6J mice.

Lateral Meningocele or Lehman Syndrome (LMS) is associated with NOTCH3 mutations causing deletions of the PEST domain and a gain-of-NOTCH3 function. We demonstrated that Notch3 mice harboring Notch3 mutations analogous to those found in LMS are osteopenic because of enhanced bone resorption. To determine the contribution of specific cell lineages to the phenotype, we created a conditional-by-inversion (Notch3) model termed Notch3 in which Cre recombination generates a Notch3 allele expressing a NOTCH3 mutant lacking the PEST domain.

Use of antisense oligonucleotides to target Notch3 in skeletal cells.

Notch receptors are determinants of cell fate and function, and play an important role in the regulation of bone development and skeletal remodeling. Lateral Meningocele Syndrome (LMS) is a monogenic disorder associated with NOTCH3 pathogenic variants that result in the stabilization of NOTCH3 and a gain-of-function. LMS presents with neurological developmental abnormalities and bone loss.

Semitendinosus vs Gracilis Grafts With 1- vs 2-Tunnel Techniques for Coracoclavicular Ligament Reconstruction: A Biomechanical Study.

Background: Despite the evolution of acromioclavicular joint surgery to a more anatomic coracoclavicular (CC) ligament reconstruction, no definitive guidance regarding the number and position of bone tunnels in the clavicle, as well as the ideal graft choice, is established.

Purpose/hypothesis: The purpose of this study was to biomechanically compare the reconstruction of the CC ligament complex between gracilis- and semitendinosus-tendon grafts in 1- and 2-tunnel techniques. It was hypothesized that the gracilis tendon graft will provide comparable primary stability in both tunnel techniques while utilizing a smaller tunnel diameter.

Role of nuclear factor of activated T cells in chondrogenesis osteogenesis and osteochondroma formation.

Purpose: Nuclear factor of activated T cells (NFATc) are transcription factors that play a function in the immune response and in osteoclast differentiation. In the present work, we define the function of NFATc2 in chondrogenic and osteogenic cells.

Methods: Nfatc2 and Nfatc1;Nfatc2 conditional mice were crossed with Prx1-Cre transgenics to inactivate Nfatc2 singly and with Nfatc1.

Hairy and enhancer of split 1 is a primary effector of NOTCH2 signaling and induces osteoclast differentiation and function.

Notch2 mice, which harbor a mutation replicating that found in Hajdu-Cheney syndrome, exhibit marked osteopenia because of increased osteoclast number and bone resorption. Hairy and enhancer of split 1 (HES1) is a Notch target gene and a transcriptional modulator that determines osteoclast cell fate decisions. Transcript levels of Hes1 increase in Notch2 bone marrow-derived macrophages (BMMs) as they mature into osteoclasts, suggesting a role in osteoclastogenesis.

Biconcave glenoids show 3 differently oriented posterior erosion patterns.

Background: Posterior glenoid wear remains a challenge in anatomic and reverse total shoulder arthroplasty (rTSA) because of an asymmetric erosion with altered retroversion. The purpose of this study was to assess glenoid morphology and evaluate the influence of acromial orientation in posterior glenoid erosion patterns by using 3-dimensional (3D) models.

Material And Methods: Computed tomographic (CT) shoulder scans from 3 study centers of patients awaiting rTSA between 2017 and 2018 were converted into 3D models and analyzed by 2 observers.

Nearly One-Third of Published Systematic Reviews and Meta-analyses Yield Inconclusive Conclusions: A Systematic Review.

Purpose: To perform a systematic review that determines the percentage of published orthopedic surgery and sports medicine systematic reviews and meta-analyses that have a conclusive conclusion.

Methods: A systematic review was performed using PRISMA guidelines. Six high-quality orthopedics journals were chosen for analysis over a 10-year eligibility period.

Activation of Notch3 in osteoblasts/osteocytes causes compartment-specific changes in bone remodeling.

Notch receptors maintain skeletal homeostasis. NOTCH1 and 2 have been studied for their effects on bone remodeling. Although NOTCH3 plays a significant role in vascular physiology, knowledge about its function in other cellular environments, including bone, is limited.