Functional Reach Test, Single-Leg Stance Test, and Tinetti Performance-Oriented Mobility Assessment for the Prediction of Falls in Older Adults: A Systematic Review.

OBJECTIVE: The authors sought to systematically review the existing literature on the falls-related diagnostic test properties of the Functional Reach Test (FRT), single-leg stance test (SLST), and Tinetti Performance-Oriented Mobility Assessment (POMA) in older adults across settings and patient populations. METHODS: The PubMed, EMBASE, and CINAHL databases were searched (inception-July 2020). Inclusion criteria were participants aged 60 years or more, prospectively recorded falls, and the reporting of falls-related predictive validity. Manuscripts not published in English were excluded. Methodological quality of reporting was assessed using the Tooth Scale. RESULTS: Of 1071 studies reviewed, 21 met the inclusion criteria (12 POMA, 8 FRT, 6 SLST). Seven studies (58.3%) used a modified version of the POMA, and 3 (37.5%) used a modified FRT. For the outcome of any fall, the respective ranges of sensitivity and specificity were 0.076 to 0.615 and 0.695 to 0.97 for the POMA, 0.27 to 0.70 and 0.52 to 0.83 for the modified POMA, 0.73 and 0.88 for the FRT, 0.47 to 0.682 and 0.59 to 0.788 for the modified FRT, and 0.51 and 0.61 for the SLST in community-dwelling older adults. For the SLST, the sensitivity and specificity for recurrent falls in the community-dwelling setting were 0.33 and 0.712, respectively. CONCLUSION: All the clinical tests of balance demonstrated an overall low diagnostic accuracy and a consistent inability to correctly identify fallers. None of these tests individually are able to predict future falls in older adults. Future research should develop a better understanding of the role that clinical tests of balance play in the comprehensive assessment of falls risk in older adults. IMPACT: Neither the FRT, SLST, nor POMA alone shows consistent evidence of being able to correctly identify fallers across fall types, settings, or older adult subpopulations. These clinical tests of balance cannot substitute a comprehensive falls risk assessment and thus should be incorporated in practice solely to identify and track balance impairment in older adults.

MMP13 and TIMP1 are functional markers for two different potential modes of action by mesenchymal stem/stromal cells when treating osteoarthritis.

Mesenchymal stem cells (MSCs) have been investigated as a potential injectable therapy for the treatment of knee osteoarthritis, with some evidence of success in preliminary human trials. However, optimization and scale-up of this therapeutic approach depends on the identification of functional markers that are linked to their mechanism of action. One possible mechanism is through their chondrogenic differentiation and direct role in neo-cartilage synthesis. Alternatively, they could remain undifferentiated and act through the release of trophic factors that stimulate endogenous repair processes within the joint. Here, we show that extensive in vitro aging of bone marrow-derived human MSCs leads to loss of chondrogenesis but no reduction in trophic repair, thereby separating out the two modes of action. By integrating transcriptomic and proteomic data using Ingenuity Pathway Analysis, we found that reduced chondrogenesis with passage is linked to downregulation of the FOXM1 signaling pathway while maintenance of trophic repair is linked to CXCL12. In an attempt at developing functional markers of MSC potency, we identified loss of mRNA expression for MMP13 as correlating with loss of chondrogenic potential of MSCs and continued secretion of high levels of TIMP1 protein as correlating with the maintenance of trophic repair capacity. Since an allogeneic injectable osteoar therapy would require extensive cell expansion in vitro, we conclude that early passage MMP13+ , TIMP1-secretinghigh MSCs should be used for autologous OA therapies designed to act through engraftment and chondrogenesis, while later passage MMP13- , TIMP1-secretinghigh MSCs could be exploited for allogeneic OA therapies designed to act through trophic repair.

The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation.

Multipotent mesenchymal stem cells (MSCs) have enormous potential in tissue engineering and regenerative medicine. However, until now, their development for clinical use has been severely limited as they are a mixed population of cells with varying capacities for lineage differentiation and tissue formation. Here, we identify receptor tyrosine kinase-like orphan receptor 2 (ROR2) as a cell surface marker expressed by those MSCs with an enhanced capacity for cartilage formation. We generated clonal human MSC populations with varying capacities for chondrogenesis. ROR2 was identified through screening for upregulated genes in the most chondrogenic clones. When isolated from uncloned populations, ROR2+ve MSCs were significantly more chondrogenic than either ROR2-ve or unfractionated MSCs. In a sheep cartilage-repair model, they produced significantly more defect filling with no loss of cartilage quality compared with controls. ROR2+ve MSCs/perivascular cells were present in developing human cartilage, adult bone marrow, and adipose tissue. Their frequency in bone marrow was significantly lower in patients with osteoarthritis (OA) than in controls. However, after isolation of these cells and their initial expansion in vitro, there was greater ROR2 expression in the population derived from OA patients compared with controls. Furthermore, osteoarthritis-derived MSCs were better able to form cartilage than MSCs from control patients in a tissue engineering assay. We conclude that MSCs expressing high levels of ROR2 provide a defined population capable of predictably enhanced cartilage production. Stem Cells 2017;35:2280-2291.

Repair of Torn Avascular Meniscal Cartilage Using Undifferentiated Autologous Mesenchymal Stem Cells: From In Vitro Optimization to a First-in-Human Study.

Meniscal cartilage tears are common and predispose to osteoarthritis (OA). Most occur in the avascular portion of the meniscus where current repair techniques usually fail. We described previously the use of undifferentiated autologous mesenchymal stem cells (MSCs) seeded onto a collagen scaffold (MSC/collagen-scaffold) to integrate meniscal tissues in vitro. Our objective was to translate this method into a cell therapy for patients with torn meniscus, with the long-term goal of delaying or preventing the onset of OA. After in vitro optimization, we tested an ovine-MSC/collagen-scaffold in a sheep meniscal cartilage tear model with promising results after 13 weeks, although repair was not sustained over 6 months. We then conducted a single center, prospective, open-label first-in-human safety study of patients with an avascular meniscal tear. Autologous MSCs were isolated from an iliac crest bone marrow biopsy, expanded and seeded into the collagen scaffold. The resulting human-MSC/collagen-scaffold implant was placed into the meniscal tear prior to repair with vertical mattress sutures and the patients were followed for 2 years. Five patients were treated and there was significant clinical improvement on repeated measures analysis. Three were asymptomatic at 24 months with no magnetic resonance imaging evidence of recurrent tear and clinical improvement in knee function scores. Two required subsequent meniscectomy due to retear or nonhealing of the meniscal tear at approximately 15 months after implantation. No other adverse events occurred. We conclude that undifferentiated MSCs could provide a safe way to augment avascular meniscal repair in some patients. Registration: EU Clinical Trials Register, 2010-024162-22. Stem Cells Translational Medicine 2017;6:1237-1248.

Changes in Chondrogenic Progenitor Populations Associated with Aging and Osteoarthritis.

Chondrogenic progenitor populations, including mesenchymal stem cells, represent promising cell-based transplantation or tissue engineering therapies for the regeneration of damaged cartilage. Osteoarthritis (OA) predominantly affects the elderly and is a leading cause of disability worldwide. Advancing age is a prominent risk factor that is closely associated with the onset and progression of the disease. Understanding the influence that aging and OA have on chondrogenic progenitor cells is important to determine how these processes affect the cellular mechanisms of the cells and their capacity to differentiate into functional chondrocytes for use in therapeutic applications. Here, we review the effect of age- and OA-related changes on the growth kinetics and differentiation potential of chondrogenic progenitor cell populations. Aging differentially influences the proliferative potential of progenitor cells showing reduced growth rates with increased senescence and apoptotic activity over time, while chondrogenesis appears to be independent of donor age. Cartilage tissue affected by OA shows evidence of progenitor populations with some potential for repair, however reports on the proliferative propensity of mesenchymal stem cells and their chondrogenic potential are contradictory. This is likely attributed to the narrow age ranges of samples assessed and deficits in definitively identifying donors with OA versus healthy patients across a wide scope of advancing ages. Further studies that investigate the mechanistic effects of chondrogenic progenitor populations associated with aging and the progression of OA using clearly defined criteria and age-matched control subject groups are crucial to our understanding of the clinical relevance of these cells for use in cartilage repair therapies.

Human fetal and adult bone marrow-derived mesenchymal stem cells use different signaling pathways for the initiation of chondrogenesis.

Cartilage injuries and osteoarthritis are leading causes of disability in developed countries. The regeneration of damaged articular cartilage using cell transplantation or tissue engineering holds much promise but requires the identification of an appropriate cell source with a high proliferative propensity and consistent chondrogenic capacity. Human fetal mesenchymal stem cells (MSCs) have been isolated from a range of perinatal tissues, including first-trimester bone marrow, and have demonstrated enhanced expansion and differentiation potential. However, their ability to form mature chondrocytes for use in cartilage tissue engineering has not been clearly established. Here, we compare the chondrogenic potential of human MSCs isolated from fetal and adult bone marrow and show distinct differences in their responsiveness to specific growth factors. Transforming growth factor beta 3 (TGFß3) induced chondrogenesis in adult but not fetal MSCs. In contrast, bone morphogenetic protein 2 (BMP2) induced chondrogenesis in fetal but not adult MSCs. When fetal MSCs co-stimulated with BMP2 and TGFß3 were used for cartilage tissue engineering, they generated tissue with type II collagen and proteoglycan content comparable to adult MSCs treated with TGFß3 alone. Investigation of the TGFß/BMP signaling pathway showed that TGFß3 induced phosphorylation of SMAD3 in adult but not fetal MSCs. These findings demonstrate that the initiation of chondrogenesis is modulated by distinct signaling mechanisms in fetal and adult MSCs. This study establishes the feasibility of using fetal MSCs in cartilage repair applications and proposes their potential as an in vitro system for modeling chondrogenic differentiation and skeletal development studies.