With very few exceptions, all adult tissues in mammals are maintained and can be renewed by stem cells that self-renew and generate the committed progeny required. These functions are regulated by a specific and in many ways unique microenvironment in stem cell niches. In most cases disruption of an adult stem cell niche leads to depletion of stem cells, followed by impairment of the ability of the tissue in question to maintain its functions. The presence of stem cells, often referred to as mesenchymal stem cells (MSCs) or multipotent bone marrow stromal cells (BMSCs), in the adult skeleton has long been realized. In recent years there has been exceptional progress in identifying and characterizing BMSCs in terms of their capacity to generate specific types of skeletal cells in vivo . Such BMSCs are often referred to as skeletal stem cells (SSCs) or skeletal stem and progenitor cells (SSPCs), with the latter term being used throughout this review. SSPCs have been detected in the bone marrow, periosteum, and growth plate and characterized in vivo on the basis of various genetic markers (i.e., Nestin, Leptin receptor, Gremlin1, Cathepsin-K, etc.). However, the niches in which these cells reside have received less attention. Here, we summarize the current scientific literature on stem cell niches for the SSPCs identified so far and discuss potential factors and environmental cues of importance in these niches in vivo . In this context we focus on (i) articular cartilage, (ii) growth plate cartilage, (iii) periosteum, (iv) the adult endosteal compartment, and (v) the developing endosteal compartment, in that order.

Growth plate and articular cartilage constitute a single anatomical entity early in development but later separate into two distinct structures by the secondary ossification center (SOC). The reason for such separation remains unknown. We found that evolutionarily SOC appears in animals conquering the land - amniotes. Analysis of the ossification pattern in mammals with specialized extremities (whales, bats, jerboa) revealed that SOC development correlates with the extent of mechanical loads. Mathematical modeling revealed that SOC reduces mechanical stress within the growth plate. Functional experiments revealed the high vulnerability of hypertrophic chondrocytes to mechanical stress and showed that SOC protects these cells from apoptosis caused by extensive loading. Atomic force microscopy showed that hypertrophic chondrocytes are the least mechanically stiff cells within the growth plate. Altogether, these findings suggest that SOC has evolved to protect the hypertrophic chondrocytes from the high mechanical stress encountered in the terrestrial environment.

46Growth plates are narrow discs of cartilage, ultimately required for longitudinal growth 47 of all mammals including humans. However, originally the growth plate and articular 48 cartilage were a single anatomical entity, an epiphyseal cartilage, as appeared in early 49 tetrapods and in mammalian development. The reason, why the growth plates evolved 50 as spatially separate organs, remains unknown. 51Here, we demonstrate that the epiphyseal growth plate first appeared as an 52individual organ in amniotes due to the formation of a novel bony structure, the 53 secondary ossification center (SOC), which spatially separates articular cartilage and 54 the growth plate. Since amniotes translocate their entire growth period on land, we next 55 explored the role of mechanical demands faced by bones growing under weight-bearing 56conditions. Comparison of mammals whose limbs are subjected to greater or lesser 57 mechanical demands (i.e., Chiropterans (bats), Cetaceans (whales) and Dipodidae 58(jerboa)) revealed that the presence of an SOC is correlated to the extent of these 59 demands. Mathematical modelling in combination with physical and biological 60 experiments showed that the SOC reduces shear and normal stresses within the growth 61 plate, allowing epiphyseal chondrocytes to withstand a six-fold higher load before 62 undergoing caspase-dependent apoptosis via the YAP-p73 pathway. Furthermore, the 63 hypertrophic chondrocytes, the cells primarily responsible for bone elongation were 64 least mechanically stiff and most sensitive to weight bearing. 65Our results demonstrate that evolution of the epiphyseal cartilage into a 66 separate organ allows epiphyseal chondrocytes to withstand the high mechanical stress 67 placed on them by the terrestrial environment. 68 69 70Main text 71 72The skeleton articulates via articular cartilage and grow in length via the 73 epiphyseal cartilage, often presented as growth plates, tiny discs of cartilage located to 74 the end of long bones and containing epiphyseal chondrocytes. These chondrocytes 75 proliferate, align in the longitudinal direction and then undergo several-fold of 76 enlargement (hypertrophy). Thereafter hypertrophic chondrocytes undergo apoptosis 77 or trans-differentiation 1 leaving their calcified extracellular matrix as a scaffold for 78invading blood vessels and osteoblasts to form new bone tissue. The process of bone 79 growth on cartilage template is called endochondral bone formation. Recent 3D 80 microanatomical characterization of the 380-million-year-old lobe-finned fish 81Eusthenopteron 2 revealed longitudinally-oriented trabeculae within the shaft of their 82 humeri ( Fig.

Damaged hyaline cartilage gradually decreases joint function and growing pain significantly reduces the quality of a patient’s life. The clinically approved procedure of autologous chondrocyte implantation (ACI) for treating knee cartilage lesions has several limits, including the absence of healthy articular cartilage tissues for cell isolation and difficulties related to the chondrocyte expansion in vitro. Today, various ACI modifications are being developed using autologous chondrocytes from alternative sources, such as the auricles, nose and ribs. Adult stem cells from different tissues are also of great interest due to their less traumatic material extraction and their innate abilities of active proliferation and chondrogenic differentiation. According to the different adult stem cell types and their origin, various strategies have been proposed for stem cell expansion and initiation of their chondrogenic differentiation. The current review presents the diversity in developing applied techniques based on autologous adult stem cell differentiation to hyaline cartilage tissue and targeted to articular cartilage damage therapy.

Growth plate and articular cartilage constitute a single anatomical entity early in development but later separate into two distinct structures by the secondary ossification center (SOC). The reason for such separation remains unknown. We found that evolutionarily SOC appears in animals conquering the land -amniotes. Analysis of the ossification pattern in mammals with specialized extremities (whales, bats, jerboa) revealed that SOC development correlates with the extent of mechanical loads. Mathematical modeling revealed that SOC reduces mechanical stress

<abstract> <p>Mast cells are best known for their involvement in the pathogenesis of allergic reactions and inflammation. Due to the wide variety of activation methods and the various mediators that mast cells can synthesize and store, they can regulate all stages of the inflammatory process. There are a large amount of data describing the role of mast cells in the development of autoimmune rheumatoid arthritis, but their role in the development of inflammatory traumatic osteoarthritis remains poorly described. However, non-autoimmune cartilage damage is the main reason for joint replacement surgeries. As important regulators of the inflammatory process, mast cells could be an interesting target for the treatment of osteoarthritis. Herein, we summarize the knowledge about the role of mast cells in the pathogenesis of osteoarthritis and outline various approaches that, to varying degrees, seem promising for the correction of the disease.</p> </abstract>

Articular cartilage has a limited capacity for self-repair and clinical approaches to cartilage regeneration are needed. The only such approach developed to date involves an expansion of primary autologous chondrocytes in culture, followed by their reimplantation into a cartilage defect. However, because of the formation of fibrocartilage instead of hyaline cartilage, the outcome is often not satisfactory. It happens due to the de-differentiation of chondrocytes during the expansion step. Indeed, articular chondrocytes are non-proliferative and require partial or complete dedifferentiation before actively proliferating. In recent years stem/progenitor cells in articular cartilage (artSPCs) have been described. These cells maintain their own population and renew articular cartilage in sexually mature mice. artSPCs can, theoretically, be superior to chondrocytes, for repairing damaged cartilage. Accordingly, here, we searched for conditions that allow rapid expansion of both artSPCs and chondrocytes with simultaneous preservation of their ability to form hyaline cartilage. Among the modulators of Wnt, Notch, and FGF signaling and of cell adhesion screened, only fibronectin and modulators of the Notch pathway promoted the rapid expansion of artSPCs. Surprisingly, both inhibition and activation of the pathway had this effect. However, only inhibition of Notch during expansion facilitated the chondrogenic potential of both artSPCs and primary chondrocytes, whereas activation of this pathway abrogated this potential entirely. This effect was the same for murine and human cells. Our present observations indicate that Notch signaling is the major regulator of the chondrogenic capacity of both artSPCs and chondrocytes during their expansion.

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