Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

Osteoarthritis is the most common musculoskeletal disease causing chronic disability in adults. Studying cartilage aging, chondrocyte senescence, inflammation, and autophagy mechanisms have identified promising targets and pathways with clinical translatability potential. In this review, we highlight the most recent mechanistic and therapeutic preclinical models of aging with particular relevance in the context of articular cartilage and OA. Evidence supporting the role of metabolism, nuclear receptors and transcription factors, cell senescence, and circadian rhythms in the development of musculoskeletal system degeneration assure further translational efforts. This information might be useful not only to propose hypothesis and advanced models to study the molecular mechanisms underlying joint degeneration, but also to translate our knowledge into novel disease-modifying therapies for OA

Proliferation and differentiation potential of canine synovial fluid cells

The aim of this study was to determine whether synovial fluid (SF) of dogs contains cells that have characteristics of MSCs and to describe their differentiation potential. SF adherent cells from 5 young German shepherd dogs (average 3.8 +/- 0.9 years) were expanded (37 degrees C, 5% CO2, humidified atmosphere) three weeks before their phenotype was characterized by flow-cytometry for the presence of CD90 and CD34. Population doubling time (PDT), number of CFU-F and adipogenic, osteogenic and chondrogenic potentials have been determined in vitro. In early passages PTD was 31 +/- 10 hours and expansion fold after 3 sub cultivations (9 days) theoretically could be 372 +/- 134. At P1, 0.55 +/- 0.05% of SF cells had the ability to form CFU-F. Sixty-six percent of cells expressed CD90 and none of the cells expressed markers of hematopoietic cells. Oil Red O staining has shown accumulation of fat droplets in cells grown in adipogenic medium, while deposits of calcium in the osteogenic medium were evidenced with Alizarin red staining. SF cultured in hondrogenic and control medium in three-dimensional conditions formed a cartilage-like tissue. Alcian blue staining of pellets' slides have shown a significant amount of glycosaminoglycans (GAGs) and immunohistochemistry analysis documented collagen type II expression. The amount of GAGs in pellets grown in both conditions showed no difference. SF cells in vitro exhibited osteogenic, adipogenic and chondrogenic differentiation potentials, suggesting the presence of different mesenchymal progenitors. These results also demonstrated that SF cells have a spontaneous chondrogenic potential that should be further explored for possible tissue engineering protocols

Effect of subclinical and overt form of rat maternal hypothyroidism on offspring endochondral bone formation

Maternal hypothyroidism in its overt form affects skeletal development of the offspring, but these data are not available for the subclinical form which is becoming very frequent among pregnant women. We hypothesized that the subclinical form of hypothyroidism in rat dams, influences the process of offspring endochondral ossification affecting proliferation and differentiation of chondrocytes, osteoclasts and osteoblasts in pups. Seven-day-old male pups (n=18) derived from control dams and dams treated with a low dose (1.5 mg/L) or high dose (150 mg/L) of propylthiouracil in drinking water during pregnancy and lactation were used. Histomorphometric analysis of pups tibia proximal growth plate, expression of mRNA, immunohistochemical and histochemical visualization of extracellular matrix components was performed. The length of the tibia was reduced in hypothyroid pups. Secretion of type 2 and 10 collagens in the subclinical and overt form were lower while the amount of glycosaminoglycans was higher when compared with controls. Down-regulated tartrate resistant acid phosphatase mRNA indicated altered osteoclasts function while lower expression of dentin matrix acid protein-1 mRNA and reduced synthesis of type 1 collagen accentuated a compromised bone formation in the overt form of hypothyroidism. The subclinical form of maternal hypothyroidism had a negative effect on the differentiation of hypertrophic chondrocytes and calcified cartilage removal in 7-day-old pups. In addition, overt hypothyroidism had a negative effect on the proliferation of chondrocytes and deposition of osteoid. Both forms of hypothyroidism resulted in a decrease of tibia length due to changes in growth plate formation

Notochordal cell-based treatment strategies and their potential in intervertebral disc regeneration

Chronic low back pain is the number one cause of years lived with disability. In about 40% of patients, chronic lower back pain is related to intervertebral disc (IVD) degeneration. The standard-of-care focuses on symptomatic relief, while surgery is the last resort. Emerging therapeutic strategies target the underlying cause of IVD degeneration and increasingly focus on the relatively overlooked notochordal cells (NCs). NCs are derived from the notochord and once the notochord regresses they remain in the core of the developing IVD, the nucleus pulposus. The large vacuolated NCs rapidly decline after birth and are replaced by the smaller nucleus pulposus cells with maturation, ageing, and degeneration. Here, we provide an update on the journey of NCs and discuss the cell markers and tools that can be used to study their fate and regenerative capacity. We review the therapeutic potential of NCs for the treatment of IVD-related lower back pain and outline important future directions in this area. Promising studies indicate that NCs and their secretome exerts regenerative effects, via increased proliferation, extracellular matrix production, and anti-inflammatory effects. Reports on NC-like cells derived from embryonic- or induced pluripotent-stem cells claim to have successfully generated NC-like cells but did not compare them with native NCs for phenotypic markers or in terms of their regenerative capacity. Altogether, this is an emerging and active field of research with exciting possibilities. NC-based studies demonstrate that cues from developmental biology can pave the path for future clinical therapies focused on regenerating the diseased IVD

Osteoarthritis: from pathogenic mechanisms and recent clinical developments to novel prospective therapeutic options.

International audienceOsteoarthritis (OA) is a degenerative joint disease that, despite recent progress, has no curative treatment. Considerable research has recently been initiated to identify new potential therapeutic targets. In this review, we will set forth some of the major discoveries in the past 5 years, notably those dealing with the identification of pathogenic factors [hypoxia-inducible factors (HIFs), complement, transforming growth factor (TGF)-β and zinc-ZIP8]. New drugs and concepts currently in clinical development [anti-nerve growth factor (NGF), mesenchymal stromal cells and fibroblast growth factor (FGF)-18] will then be addressed. Finally, we will consider prospective avenues that could lead to mid-to-long-term developments of novel therapeutic concepts, notably those dealing with autophagy regulation and induced pluripotent stem cells

Calcium phosphate biomaterials as bone drug delivery systems: a review

A short review is proposed on the existing literature for the research performed in calcium phosphate (CaP) biomaterials used as drug delivery systems. In the first part, a brief update is given on the performance of both CaP ceramics and CaP cements. Second, a review of the research and clinical situation is developed for CaP materials already used as drug delivery systems. Experimental works performed for local delivery are reported. In particular, a description is given of the in vitro and in vivo studies in which these materials are loaded with various proteins and drugs

Putative role of Caspase-3 during mesenchymal stem cells differentiation

National audienc

Putative role of Caspase-3 during mesenchymal stem cells differentiation

National audienc

Putative role of Caspase-3 during mesenchymal stem cells differentiation

National audienc

Na-doped beta-tricalcium phosphate: physico-chemical and in vitro biological properties

Synthetic calcium phosphate ceramics as beta-tricalcium phosphate (Ca-3(PO4)(2); beta-TCP) are currently successfully used in human bone surgery. The aim of this work was to evaluate the influence of the presence of sodium ion in beta-TCP on its mechanical and biological properties. Five Na-doped-beta-TCP [Ca10.5-x/2Na (x) (PO4)(7), 0 <= x <= 1] microporous pellets were prepared via solid phase synthesis, and their physico-chemical data (lattice compacity, density, porosity, compressive strength, infrared spectra) denote an increase of the mechanical properties and a decrease of the solubility when the sodium content is raised. On the other hand, the in vitro study of MC3T3-E1 cell activity (morphology, MTS assay and ALP activity) shows that the incorporation of sodium does not modify the bioactivity of the beta-TCP. These results strongly suggest that Na-doped-beta-TCP appear to be good candidates for their use as bone substitutes