Mechanisms of synovial joint and articular cartilage formation: Recent advances, but many lingering mysteries

Abstract

Synovial joints are elegant, critically important, and deceptively simple biomechanical structures. They are comprised of articular cartilage that covers each end of the opposing skeletal elements, synovial fluid that lubricates and nourishes the tissues, ligaments that hold the skeletal elements in check, and a fibrous capsule that insulates the joints from surrounding tissues. Joints also exhibit an exquisite arrays of shapes and sizes, best exemplified by the nearly spherical convex femoral head articulating into a nearly spherical concave hip acetabulum, or a phalangeal joint with two condyles on the distal side articulating in reciprocally-shaped sockets on the opposing proximal side. Though few in number, joint tissues are highly specialized in structure and function. This is illustrated by articular cartilage with its unique extracellular matrix, unique biomechanical resilience, its largely avascular nature, and its ability to persist through life with minimal turnover of its cells and components. The fact that interest in synovial joints has remained unabated for decades is a reflection of their fundamental importance for organism function and quality of life, and for their susceptibility to a variety of acquired and congenital conditions, most importantly arthritis. This has led to many advances in this field that encompass molecular genetics to biomechanics to medicine. Regrettably, what continues to be poorly understood are the mechanisms by which synovial joints actually form in the developing embryo. If available, this information would be not only of indisputable biological interest, but would also have significant biomedical ramifications, particularly in terms of designing novel tissue regeneration or reconstruction therapies. This review focuses on recent advances in understanding the mechanisms of synovial joint formation in the limbs, and places and discusses the information within the context of classic studies and the many mysteries and questions that remain unanswered.

CDMP1/GDF5 Has Specific Processing Requirements That Restrict Its Action to Joint Surfaces

“…Such a restricted pattern of GDF5 activity provides for its specific function in the morphogenesis of individual joints. It is well established that during joint formation the proximal and distal boundaries adopt "interlocking and reciprocally shaped joint sides" (40). Our finding that GDF5 is likely to be active only in discrete regions of the developing joint surface, and not within the joint space, is consistent with this concept.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…The joint interzone later divides into three discrete layers. Cells within the medial layer express BMP-2 and subsequently undergo cell death, thereby forming the joint cavity, whereas the remaining outer layers will give rise to the articular cartilage (reviewed in Pacifici et al 2005). During joint formation, noggin is expressed within the intermedial layer of the interzone (Brunet et al 1998;Capdevila and Johnson 1998;Merino et al 1998;Goumans and Mummery 2000;Pizette and Niswander 2000;Seemann et al 2005;Lorda-Diez et al 2013), where it counteracts the effect of GDF-5, the key molecule required for defining the future joint interzone within the unpatterned digital ray.…”

Recapitulation of physiological spatiotemporal signals promotes in vitro formation of phenotypically stable human articular cartilage

“…Whether bona fide articular cartilage can be formed from MSCs requires validation with welldefined markers that distinguish between mature chondrocytes and MSCs (33). Developmentally, the articular cartilage is formed by outer interzone cells originating from the chondrogenic mesoderm (16). The use of pluripotent stem cells would also enable unprecedented control, as they can generate chondrocytes with distinct articular and growth plate phenotypes (34).…”

“…Cartilage formed by MSCs is poorly organized and prone to endochondral ossification in vivo (4,15). Instead, the native articular cartilage is organized and comprises the superficial zone, which develops into permanent cartilage, and the deep zone, which mineralizes to form calcified cartilage (16). We hypothesized that the implementation of spatiotemporal regulation during induction of self-assembling human (h)MSCs in vitro can potentiate the formation of functional cartilage with physiologic organization and in vivo stability.…”