Clinical validation of CFDG as a marker associated with senescence and osteoarthritic phenotypes.

Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro-inflammatory senescence-associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age-related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss.

A modified Delphi consensus statement on patellar instability: part I.

Aims: The aim of this study was to establish consensus statements on the diagnosis, nonoperative management, and indications, if any, for medial patellofemoral complex (MPFC) repair in patients with patellar instability, using the modified Delphi approach.

Methods: A total of 60 surgeons from 11 countries were invited to develop consensus statements based on their expertise in this area. They were assigned to one of seven working groups defined by subtopics of interest within patellar instability.

A modified Delphi consensus statement on patellar instability: part II.

Aims: The aim of this study was to establish consensus statements on medial patellofemoral ligament (MPFL) reconstruction, anteromedialization tibial tubercle osteotomy, trochleoplasty, and rehabilitation and return to sporting activity in patients with patellar instability, using the modified Delphi process.

Methods: This was the second part of a study dealing with these aspects of management in these patients. As in part I, a total of 60 surgeons from 11 countries contributed to the development of consensus statements based on their expertise in this area.

Bioprinted Notch ligand to function as stem cell niche improves muscle regeneration in dystrophic muscle.

299In Duchenne muscular dystrophy, dystrophic muscle phenotypes are closely associated with the exhaustion of muscle stem cells. Transplantation of muscle stem cells has been widely studied for improving muscle regeneration, but poor cell survival and self-renewal, rapid loss of stemness, and limited dispersion of grafted cells following transplantation have collectively hindered the overall success of this strategy. Optimized mechanisms for maintaining and improving stem cell function are naturally present in the microenvironment of the stem cell niche in healthy muscles.

Nuclear softening mediated by Sun2 suppression delays mechanical stress-induced cellular senescence.

Nuclear decoupling and softening are the main cellular mechanisms to resist mechanical stress-induced nuclear/DNA damage, however, its molecular mechanisms remain much unknown. Our recent study of Hutchinson-Gilford progeria syndrome (HGPS) disease revealed the role of nuclear membrane protein Sun2 in mediating nuclear damages and cellular senescence in progeria cells. However, the potential role of Sun2 in mechanical stress-induced nuclear damage and its correlation with nuclear decoupling and softening is still not clear.

The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Progeria Mouse Model.

Aging leads to several geriatric conditions including osteoporosis (OP) and associated frailty syndrome. Treatments for these conditions are limited and none target fundamental drivers of pathology, and thus identifying strategies to delay progressive loss of tissue homeostasis and functional reserve will significantly improve quality of life in elderly individuals. A fundamental property of aging is the accumulation of senescent cells.

Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel.

Salivary gland acinar cells are severely depleted after radiotherapy for head and neck cancer, leading to loss of saliva and extensive oro-digestive complications. With no regenerative therapies available, organ dysfunction is irreversible. Here, using the adult murine system, we demonstrate that radiation-damaged salivary glands can be functionally regenerated via sustained delivery of the neurogenic muscarinic receptor agonist cevimeline.

Senolytic elimination of senescent macrophages restores muscle stem cell function in severely dystrophic muscle.

The aging of the immune system, or immunosenescence, was recently verified to have a causal role in driving the aging of solid organs, while the senolytic elimination of senescent immune cells was found to effectively delay systemic aging. Our recent study also showed that immune cells in severely dystrophic muscles develop senescence-like phenotypes, including the increased expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Here we further investigated whether the specific clearance of senescent immune cells in dystrophic muscle may effectively improve the function of muscle stem cells and the phenotypes of dystrophic muscle.

Current State of Platelet-Rich Plasma and Cell-Based Therapies for the Treatment of Osteoarthritis and Tendon and Ligament Injuries.

➤: Orthobiologics encompass numerous substances that are naturally found in the human body including platelet-rich plasma (PRP), isolated growth factors, and cell therapy approaches to theoretically optimize and improve the healing of cartilage, fractures, and injured muscles, tendons, and ligaments.

➤: PRP is an autologous derivative of whole blood generated by centrifugation and is perhaps the most widely used orthobiologic treatment modality. Despite a vast amount of literature on its use in osteoarthritis as well as in tendon and ligament pathology, clinical efficacy results remain mixed, partly as a result of insufficient reporting of experimental details or exact compositions of PRP formulations used.

Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging.

Constitutive NF-κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF-κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF-κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models.

Comparison of Autologous Blood Clots with Fibrin Sealant as Scaffolds for Promoting Human Muscle-Derived Stem Cell-Mediated Bone Regeneration.

. Fibrin sealant has been used as a scaffold to deliver genetically modified human muscle-derived stem cells (hMDSCs) for bone regeneration. Alternatively, autologous blood clots are safe, economic scaffolds.

The Beneficial Effect of an Intra-articular Injection of Losartan on Microfracture-Mediated Cartilage Repair Is Dose Dependent.

Background: A previous publication demonstrated that the oral intake of losartan promoted microfracture-mediated hyaline-like cartilage repair in osteochondral defects of a rabbit knee model. However, an intra-articular (IA) injection of losartan may have direct beneficial effects on cartilage repair and has not been studied.

Purpose: To determine the dosage and beneficial effects of an IA injection of losartan on microfracture-mediated cartilage repair and normal cartilage homeostasis.

Intra-articular Injection of Bevacizumab Enhances Bone Marrow Stimulation-Mediated Cartilage Repair in a Rabbit Osteochondral Defect Model.

Background: Bone marrow stimulation (BMS) via microfracture historically has been a first-line treatment for articular cartilage lesions. However, BMS has become less favorable because of resulting fibrocartilage formation. Previous studies have shown that angiogenesis blockade promotes cartilage repair.

Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice.

Duchenne Muscular Dystrophy (DMD) patients often suffer from both muscle wasting and osteoporosis. Our previous studies have revealed reduced regeneration potential in skeletal muscle and bone, concomitant with ectopic calcification of soft tissues in double knockout (, ; utrophin-/-) mice, a severe murine model for DMD. We found significant involvement of RhoA/ROCK (Rho-Associated Protein Kinase) signaling in mediating ectopic calcification of muscles in mice.

Receptor mimicking TGF-β1 binding peptide for targeting TGF-β1 signaling.

Prolonged and elevated transforming growth factor-β1 (TGF-β1) signaling can lead to undesired scar formation during tissue repair and fibrosis that is often a result of chronic inflammation in the lung, kidney, liver, heart, skin, and joints. We report new TGF-β1 binding peptides that interfere with TGF-β1 binding to its cognate receptors and thus attenuate its biological activity. We identified TGF-β1 binding peptides from the TGF-β1 binding domains of TGF-β receptors and engineered their sequences to facilitate chemical conjugation to biomaterials using molecular docking simulations.

Chondrocyte-to-osteoblast transformation in mandibular fracture repair.

The majority of fracture research has been conducted using long bone fracture models, with significantly less research into the mechanisms driving craniofacial repair. However, craniofacial bones differ from long bones in both their developmental mechanism and embryonic origin. Thus, it is possible that their healing mechanisms could differ.

Impaired bone defect and fracture healing in dystrophin/utrophin double-knockout mice and the mechanism.

This study investigated the role of muscle damage in bone defect healing using skull and tibial double-defect and tibial fracture models in dystrophin/Utrophin double-knockout (dKO-Hom) mice. The skull and tibia bone defect and fracture healing was monitored using micro-CT, histology, immuohistochemistry and quantitative PCR. We found the skull defect healing is not impaired while the tibial defect healing was delayed at day 7 in the dKO-Hom group compared to wild-type (WT) group as revealed by micro-CT.

Effect of Oral Losartan on Orthobiologics: Implications for Platelet-Rich Plasma and Bone Marrow Concentrate-A Rabbit Study.

Recent efforts have focused on customizing orthobiologics, such as platelet-rich plasma (PRP) and bone marrow concentrate (BMC), to improve tissue repair. We hypothesized that oral losartan (a TGF-β1 blocker with anti-fibrotic properties) could decrease TGF-β1 levels in leukocyte-poor PRP (LP-PRP) and fibrocytes in BMC. Ten rabbits were randomized into two groups (N = 5/group): osteochondral defect + microfracture (control, group 1) and osteochondral defect + microfracture + losartan (losartan, group 2).

The Life of a Fracture: Biologic Progression, Healing Gone Awry, and Evaluation of Union.

New knowledge about the molecular biology of fracture-healing provides opportunities for intervention and reduction of risk for specific phases that are affected by disease and medications. Modifiable and nonmodifiable risk factors can prolong healing, and the informed clinician should optimize each patient to provide the best chance for union. Techniques to monitor progression of fracture-healing have not changed substantially over time; new objective modalities are needed.