Cartilage has a limited healing capacity; however, studies into the basic biological characteristics, formation and structural maintenance of the cartilage collagen network are providing explanations for the failure of current therapeutic approaches, urging us to rethink our approach to the regeneration of articular cartilage.
Cartilage repair and regeneration
Articular cartilage can be damaged by trauma or degraded by different forms of arthritis. Once damaged, cartilage is challenging to repair and currently impossible to fully regenerate. Advances including the discovery of new types of skeletal stem cells and the introduction of gene therapy approaches to repair damaged cartilage are placing cartilage repair and regeneration in the spotlight.
This Collection contains Research, Reviews and News articles from several Nature journals that cover the latest advances in basic cartilage research, as well as insights into cartilage repair and potential regeneration strategies.
News and Comment
Bone elongation requires the maintenance of a growth plate of cartilage. Two studies have now identified stem cells specific to this structure that give rise to both cartilage cells and bone-marrow stem cells.
The search for the identity of skeletal stem cells has reached a point at which skeletogenic cell populations with self-renewing capacity can be enriched and studied in detail. These advances provide new hope for skeletal regenerative medicine.
After more than 25 years of development, arthritis gene therapy is finally entering clinical practice. In South Korea, a gene therapeutic has been approved for the treatment of osteoarthritis, and other gene therapeutics are in the pipeline elsewhere. Genetic medicines for arthritis should enter the rheumatological armamentarium in the foreseeable future.
Regeneration of articular cartilage has been a long-standing challenge in the field of regenerative medicine. In the past 2 years, several studies have genetically identified the presence of stem cells in the surface of articular cartilage, but questions remain as to the healing properties of these cells.
Like the mythical eagle devouring Prometheus's liver as fast as it regrew, chronic inflammation hinders cartilage regeneration in inflammatory arthritis. Using stem cells engineered to secrete anti-inflammatory molecules in response to local inflammatory factors could provide a way to keep the eagle at bay as the stem cells differentiate into chondrocytes.
Tissue engineering strategies to repair articular cartilage and menisci are advancing rapidly. This Review provides an overview of surgical and tissue engineering approaches in current use and outlines exciting developments in the field.
Improved understanding of cell migration in the synovial joint, including the associated cellular and environmental factors, might reveal new therapeutic strategies for joint diseases such as rheumatoid arthritis and osteoarthritis and have important implications for tissue engineering of the joint.
This Review discusses the factors that affect the phenotypes of mesenchymal stromal cells, and the need for standardized assays that provide quality assurance for clinical uses of the cells.
Gene therapy and tissue engineering strategies for the treatment of cartilage repair each pose unique challenges to clinical translation. Could combining the two approaches open new avenues for the treatment of articular cartilage defects in patients with osteoarthritis?
Intra-articular therapies for knee osteoarthritis (OA) are causing excitement among clinicians and patients, but care should be taken when choosing which therapy to use. In this Review, Vangsness and colleagues critically appraise current and future intra-articular therapies for knee OA.
The development of cartilage-penetrating therapies relies on an in-depth understanding of the biophysical properties of this complex tissue. In this Review, knowledge accumulated over 50 years is synthesized to reveal the key principles of solute transport in cartilage.
In the past few years, excitement has grown over the potential use of mesenchymal stem cells (MSCs) for cartilage repair, although the rarity of these cells has hampered progress. In this Review, the authors examine the potential of joint-resident MSCs as a new avenue for repair in osteoarthritis.
In this Review, the role of canonical Wnt signalling in articular cartilage is discussed, along with the regulatory mechanisms that exist to fine-tune Wnt signalling and the rationale for developing drugs that modulate Wnt signalling for the treatment of joint diseases such as osteoarthritis.
Research and Protocols
Preclinical safety study of a combined therapeutic bone wound dressing for osteoarticular regeneration
Arthroplasty is the main clinical option for the treatment of osteoarticular lesions, but has limited efficacy. Here, the authors use a wound dressing with autologous mesenchymal stromal cells, functionalised for local BMP2 delivery, and show feasibility and safety in standardised preclinical tests in animal models, suggesting suitability for use in clinical trials.
Isolation and mass spectrometry based hydroxyproline mapping of type II collagen derived from Capra hircus ear cartilage
Priti Prasanna Maity et al. develop a method for high-yield isolation of type II collagen from the Capra hircus ear cartilage, a commonly available biowaste product. Using mass spectrometry they mapped the positions of hydroxyproline within the collagen II alpha chain; this methodology facilitates isolation and characterization of this biomedical resource.
A small molecule promotes cartilage extracellular matrix generation and inhibits osteoarthritis development
Loss of cartilage tissue is a hallmark of osteoarthritis. Here the authors show that BNTA, a small molecule identified in a chemical screen, promotes ECM generation in human osteoarthritic chondrocytes and cartilage explants, and suppresses pathology in a rat model of osteoarthritis.
Clonal genetic tracing is used to demonstrate that, in mice, longitudinal bone growth during fetal and neonatal periods relies on the gradual consumption of chondroprogenitors, whereas in adults, a stem cell niche is formed allowing renewing of chondroprogenitors and leading to formation of large, stable monoclonal columns of chondrocytes.
Mammalian joints have poor regenerative capacity following amputation. Here, the authors show that in mice, stimulation of the amputation wound with BMP2 and BMP9 stimulates regeneration of a synovial joint that includes bone, cartilage and a synovial cavity.
A periosteal stem cell specialized in intramembranous bone formation has been identified and was found to be essential for normal bone development and fracture healing.
A flow cytometry–based approach using eight surface markers is used to distinguish cells of the skeletal stem cell lineage. Renal subcapsular transplantation and in vitro colony-formation assays are also described for cell characterization.
Tools to investigate a wide range of 3D microenvironmental parameters are important for understanding and controlling cell fate. Here, the authors develop hydrogels with orthogonal biochemical gradients and use this screening system to identify microenvironments that induce mesenchymal stem cell chondrogenesis.
Dense connective tissues do not easily heal, in part due to a low supply of reparative cells. Here, the authors develop a fibrous scaffold for meniscal repair that sequentially releases collagenase and a growth factor at the injury site, breaking down the extracellular matrix and recruiting endogenous cells.
Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment
Pharmacological or genetic depletion of senescent cells in the joint ameliorates osteoarthritis in mice.
Natural materials such as cartilage and skin have a combination of toughness (meaning they are hard to fracture) and stiffness (meaning they are resistant to bending) that is difficult to emulate in synthetic hydrogels. Previously reported tough hydrogels owed their toughness to their ability to deform by stretching, but they lacked stiffness. Here Joerg Tiller and colleagues create hydrogels that are both tough and stiff by generating in situ amorphous calcium phosphate nanoparticles that are homogenously distributed throughout the hydrogel matrix. The resulting structures are tougher than most water-swollen synthetic hydrogels, and are stiffer than their natural counterparts. The highly filled composite materials can even be designed to be optically transparent, and they remain stretchable even when notched with a razor blade. The researchers attribute the stiffness of these materials to the formation of a percolated network of the calcium phosphate nanoparticles throughout the hydrogel.