Osteoarthritis (OA) is the most common type of arthritis and the leading cause of disability in the United States [1]. OA alone is responsible for $3.4 to $13.2 billion in job-related costs every year in the US. [2,3] and is associated with significant healthcare utilization, deficits in quality of life, and productivity loss [4-7]. Several systemic treatments, mostly symptom-modifying rather than disease-modifying agents, are available for OA [8]. Recently published OA treatment guidelines highlight the strength of evidence for various therapies [9-12]. However, there is a real need for effective, safe, disease-modifying OA therapies that can not only effectively treat those with established OA, but also possibly delay or prevent progression in those with early OA [13]. None of the potential therapies discussed in this editorial have been approved by regulatory agencies such as the US Food and Drug Administration (FDA), and therefore these therapies are experimental.

Stem cells can differentiate into different cell lineages due to their self-renewing and clonogenic capabilities [14]. Embryonic stem cells have the capability to differentiate into any terminally differentiated cell in the body [15]. Adult stem cells were originally believed to only differentiate into tissue-specific cells. However adult stem cells may be programmed under specific signals to differentiate into other organ-specific cells with a phenotype distinct from that of the precursor. Certain barriers that exist to achieving this effectively in vivo must be overcome, namely, easy accessibility to sufficient concentration of stem cells at the site of tissue repair and generation of appropriate signals from the tissue repair site directing the cells to the site [15]. Stem cells can be administered via systemic intravascular route or a direct local implantation, such as that done to repair infracted myocardium [16,17] and in spinal cord injuries [18]. In a recent study by Mokbel et al. in BMC Musculoskeletal Disorders, labeled autologous adult stem cells suspended in hyaluronic acid were injected intra-articularly into carpal joints in an experimental arthritis induced by intra-articular (IA) Amphotericin-B in donkeys [19]. Significant improvement was noted in clinical and radiographic OA and significantly lesser histopathological changes of OA were seen in carpal joints that received IA autologous mesenchymal stem cells compared to control contralateral joints that received IA hyaluronic acid [19]. Importantly, injected stem cells were incorporated into the articular cartilage of the injected joint, as evident by their integration in the surface of the cartilage and also the interior of the cartilage. Interestingly, while some of these cells showed a chondrocyte-like phenotype indicating their differentiation, other injected cells retained spindle-like structure, characteristic of the mesenchymal origin. Previous studies have suggested that bone marrow and synovial mesenchymal stem cells have more chondrogenic potential compared to adipose or muscle mesenchymal stem cells [20]. While other studies have provided evidence that stem cells may offer potential therapeutic benefit in OA [21,22], challenges remain in the translation of this knowledge into available therapies for patients with OA. The challenges include homing of adequate number of cells in the tissues undergoing repair, long-term safety of such approaches especially those using viral vectors, the durability of the benefit, and feasibility of providing these treatments in busy practitioners' offices. Despite the challenges in bringing this potential therapy to clinic, stem cell therapy offers a revolutionary approach to the treatment of OA.

The interesting study by Mokbel et al. [18] provides additional evidence from animal models for the potential of autologous mesenchymal bone marrow stem cells as a potential future treatment for OA. Early evidence from human RCTs is also available for additional IA therapies such as IL-1β antagonists, autologous conditioned serum and botulinum toxin. Whether these approaches will translate into effective and safe therapies for humans remains to be seen. This next step will need more convincing evidence of therapeutic efficacy and safety in humans in large RCTs and correlation with improvements in disease pathophysiology, with the use of serum and joint biomarkers and/or imaging biomarkers (radiographs, magnetic resonance imaging, and so on). The future of OA therapeutics seems bright, with a lot of potential therapies targeting different mechanisms of action, different pathways and different approaches for this disabling disease.

There are no financial conflicts related to this work. JAS has received investigator-initiated research and travel grants from Takeda, Allergan and Savient; consultant fees from Takeda, Ardea, Savient, Allergan, Novartis, and URL pharmaceuticals; and is a member of the executive of OMERACT, an organization that develops outcome measures in rheumatology and receives arms-length funding from 36 companies.

JAS: Concept of the editorial, literature review, preparation of editorial, and revision of the manuscript.

JAS is a rheumatologist-epidemiologist, an Associate Professor of Medicine and Epidemiology at the University of Alabama at Birmingham and staff physician at the Birmingham Veterans Affairs Medical Center. JAS is a member of the American College of Rheumatology and serves as a committee member on the Guidelines subcommittee of the American College of Rheumatology's Quality of Care committee, Veterans Affairs Rheumatology Field Advisory Committee, and the executive committee of the Outcome Measures in Rheumatology Trials (OMERACT).