Origin and function of cartilage stem/progenitor cells in osteoarthritis

Abstract

Articular cartilage is a physiologically non-self-renewing avascular tissue with a singular cell type, the chondrocyte, which functions as the load-bearing surface of the arthrodial joint. Injury to cartilage often progresses spatiotemporally from the articular surface to the subchondral bone, leading to development of degenerative joint diseases such as osteoarthritis (OA). Although lacking intrinsic reparative ability, articular cartilage has been shown to contain a population of stem cells or progenitor cells, similar to those found in many other adult tissues, that are thought to be involved in the maintenance of tissue homeostasis. These so-called cartilage-derived stem/progenitor cells (CSPCs) have been observed in human, equine and bovine articular cartilage, and have been identified, isolated and characterized on the basis of expression of stem-cell-related surface markers, clonogenicity and multilineage differentiation ability. However, the origin and functions of CSPCs are incompletely understood. We review here the current status of CSPC research and discuss the possible origin of these cells, what role they might have in cartilage repair, and their therapeutic potential in OA.

Figure 1

Identification and stem-cell-like properties of CSPCs. CSPCs have been observed in human, equine and bovine articular cartilage. Identification, isolation and characterization of CSPCs have been based on a | expression of stem-cell-related surface markers (individually and in combination, under various conditions) and b | properties such as clonogenicity and multipotency.^,, Migratory activity of CSPCs has also been found in response to injury and in late-stage OA cartilage. Abbreviations: CSPC, cartilage stem/progenitor cell; OA, osteoarthritis.

Figure 2

CSPC distribution in normal articular cartilage and during OA pathogenesis. Schematic of healthy and OA cartilage illustrating the zonal architecture and distribution of chondrocytes and CSPCs. a | In normal adult cartilage, Notch-1-expressing CSPCs probably reside in the superficial zone. b | In response to injury, spindle-shaped CSPCs appear and migrate to the injury site. c | In early OA, characterized by loss of the superficial zone and changes to the internal structure of articular cartilage, cells express surface markers such as CD105 and CD166, and cell clusters emerge, containing cells positive for stem-cell-related markers such as Notch-1, STRO-1 and VCAM-1.^, d | In late-stage OA, characterized by continued ECM loss and chondrocyte hypertrophy, CSPCs seem to migrate throughout the articular cartilage. Abbreviations: CSPC, cartilage stem/progenitor cell; ECM, extracellular matrix; Notch-1, neurogenic locus notch homologue protein 1; OA, osteoarthritis; VCAM-1, vascular cell adhesion protein 1.

Figure 3

Schematic of degenerative disease progression in OA and possible CSPC-based therapies. a | Potential therapeutic strategies involving CSPCs in early OA could enhance the capacity of these cells for joint resurfacing, ECM production and chondroprotection. b | ECM loss and structural changes in late-stage OA cartilage enable cell passage, but several challenges and questions regarding the role of migratory CSPCs remain to be addressed. Abbreviations: BMP, bone morphogenic protein; CSPC, cartilage stem/progenitor cell; ECM, extracellular matrix; IL-Ra, IL-1 receptor antagonist; OA, osteoarthritis; TGF-β, transforming growth factor β; TIMP, tissue inhibitor of metalloproteinases.