This Title All WIREs
How to cite this WIREs title:
WIREs Dev Biol
Impact Factor: 3.883

Building and maintaining joints by exquisite local control of cell fate

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

We owe the flexibility of our bodies to sophisticated articulations between bones. Establishment of these joints requires the integration of multiple tissue types: permanent cartilage that cushions the articulating bones, synovial membranes that enclose a lubricating fluid‐filled cavity, and a fibrous capsule and ligaments that provide structural support. Positioning the prospective joint region involves establishment of an “interzone” region of joint progenitor cells within a nascent cartilage condensation, which is achieved through the interplay of activators and inhibitors of multiple developmental signaling pathways. Within the interzone, tight regulation of BMP and TGFβ signaling prevents the hypertrophic maturation of joint chondrocytes, in part through downstream transcriptional repressors and epigenetic modulators. Synovial cells then acquire further specializations through expression of genes that promote lubrication, as well as the formation of complex structures such as cavities and entheses. Whereas genetic investigations in mice and humans have uncovered a number of regulators of joint development and homeostasis, recent work in zebrafish offers a complementary reductionist approach toward understanding joint positioning and the regulation of chondrocyte fate at joints. The complexity of building and maintaining joints may help explain why there are still few treatments for osteoarthritis, one of the most common diseases in the human population. A major challenge will be to understand how developmental abnormalities in joint structure, as well as postnatal roles for developmental genes in joint homeostasis, contribute to birth defects and degenerative diseases of joints. WIREs Dev Biol 2017, 6:e245. doi: 10.1002/wdev.245 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Signaling Pathways > Cell Fate Signaling Vertebrate Organogenesis > Musculoskeletal and Vascular
Distinct modes of interzone formation. The joint interzone develops in the position of the presumptive joint and precedes articular cartilage differentiation and joint cavitation. The interzone can be generated from a single mesenchymal condensation (a, green) or through appositional growth of adjacent condensations (b). While cells outside the interzone undergo further cartilage differentiation (blue) and eventually hypertrophy and mineralize during endochondral bone development (red), cells within the interzone are maintained as immature chondrocytes at the articular surface (green flattened cells) and contribute to joint specializations such as the synovial membrane (orange). Also shown are chondrocyte progenitors within the perichondrium (blue flattened cells) and osteoblast progenitors within the periosteum (red flattened cells).
[ Normal View | Magnified View ]
Skeletal joints in zebrafish and mouse. (a) In zebrafish fry at 5 days postfertilization, well‐studied cartilaginous joints (arrows) include the jaw joint between Meckel's and palatoquadrate cartilages and the bipartite hyoid joint between hyosymplectic, interhyal, and ceratohyal cartilages. (b) In a mouse embryo at E17.5, representative joints include the shoulder and elbow joints (arrows) and interphalangeal joints (arrowheads). As in young zebrafish, these joints are largely cartilaginous at this stage. (c) The adult zebrafish skeleton is largely composed of bone and contains many types of joints (arrows), including sutures in the skull, intervertebral joints, and synovial joints in the jaw and pectoral fin. (d) The mouse skeleton at postnatal Day 21 has similar joints to zebrafish, including sutures, intervertebral discs, and synovial joints in the knee and digits (i.e., interphalangeal). Skeletons were stained with alcian blue for cartilage and alizarin red for bone. ch, ceratohyal; dr, distal radial; fe, femur; hs, hyosymplectic; ih, interhyal; M, Meckel's; pq, palatoquadrate; pr, proximal radial; t, tibia.
[ Normal View | Magnified View ]
Histological features of joints. (a) Sutures are a type of immoveable articulation between bones, with the suture mesenchyme housing progenitors for bone growth and repair. Hematoxylin and eosin staining shows comparable coronal sutures of an E16.5 mouse embryo and young adult zebrafish. (b) The intervertebral discs of mouse and zebrafish have a very different structure. In mammals (shown here for postnatal Day 15 mouse), a cartilage endplate (CE) covers each vertebra, with the disc consisting of a ring of annulus fibrosus (AF) tissue and a core of nucleus pulposus (NP) tissue. In adult zebrafish, vertebral bones (red) are separated by layers of fat that appear white upon sectioning. (c) Synovial joints are freely moveable articulations characterized by fluid‐filled cavities lined by articular hyaline cartilage. Some synovial joints, as shown in a section of the knee joint from an adult mouse, include additional specializations such as menisci (M). The adult zebrafish jaw joint has a clear articular cartilage (AC) layer and synovium (S) but no mensicus. Photos courtesy of Camilla Teng (A), Jennifer Zieba (B, mouse), and Denis Evseenko (C, mouse).
[ Normal View | Magnified View ]
Synovial specializations. Distinct patterns of cavitation of the interzone (green) can generate simple synovial joints (a) or joints with specialized structures such as menisci (b) and articular discs (c). The synovium (orange) shares many properties with the fibroblasts ensheathing the menisci and disc (purple). Bony processes (red) act as attachment points for ligaments (green), with their connection point, or enthesis, consisting of a transitional cell type.
[ Normal View | Magnified View ]
Chondrocyte fate decisions. (a) Section of the knee joint from an 8‐week‐old mouse shows that Col2a1 expression (green) is stronger in growth plate chondrocytes (arrowhead) compared to articular chondrocytes (arrow). Superficial joint chondrocytes are labeled by treatment of Prg4CreER; Rosa26:memTomato/memGFP mice with Tamoxifen three weeks earlier (anti‐GFP antibody staining detects Prg4CreER‐converted cells in red). (c) Compared to the complex mammalian knee joint, the hyoid joint of 6‐day‐old zebrafish (arrows) provides a simplified model for understanding the specification of joint chondrocyte fate. In this example, transient chondrocytes express both a sox10:dsRed transgene (red) and a col2a1a:GFP transgene (green). In contrast, joint chondrocytes express sox10 but much lower levels of col2a1a, suggesting they are immature. (c) Cells within a mesenchymal condensation initially express Barx1 and then go on to express Sox9 (and in zebrafish also the related SoxE family member sox10), Dcx, and low levels of Col2a1 (in particular an A splice isoform). In the growth plate, these cells mature into prehypertrophic chondrocytes that express high levels of Col2a1 and Matn1 and then hypertrophic chondrocytes that express Col10a1, Runx2, and other genes associated with mineralization. In contrast, interzone cells differentiate into articular chondrocytes that maintain low Col2a1 and instead express Gdf5 and later Prg4. Although Wnt9a and Fgf18 promote a joint fate, Ihh signaling controls cartilage maturation. Specification of articular chondrocyte fate is promoted through inhibition of cartilage maturation by a number of transcription factors and chromatin remodelers, including Iroquois proteins (Irx), Trps1, Nkx3.2, Cux1, Erg, Lrf, and Hdac1. (d) Under the control of signaling factors including Gdf5/6, Wnt9a, Fgf18, TGFβ and Noggin, chondroprogenitor cells mature to form the different chondrocyte layers of the growth plate (darker blue) or remain relatively immature within the joint (orange cells in light blue matrix). Factors including Trps1, Has, and Ihh then drive interzone cells to cavitate as superficial zone articular chondrocytes (brown) begin to produce lubricating molecules such as Prg4.
[ Normal View | Magnified View ]
Critical thresholds of Bmp and Tgfβ signaling in joint development. (a, b) Histological sections stained with hematoxylin and eosin show the different layers of joint cartilage in a human knee (16‐year‐old) and juvenile spotted gar jaw. (c) The levels, duration, and/or type of Bmp signaling help to specify the different types of chondrocytes at and around joints: hypertrophic, radial, transitional, and superficial. The Bmp ligands Gdf5/6/7 and antagonists Chordin (Chd), Noggin (Nog), and Gremlin2 (Grem2) are expressed in the developing interzone, and Bmp2/4/7 have been reported to be expressed either at a distance from the joint or at the joint itself. Variable diffusion of these ligands and antagonists may establish different levels of Bmp signaling, and signaling through Bmpr1a and Bmpr1b receptors could also influence joint fate. TGFβ signaling also has an important role to specify joint fates, with the Tgfbr2 receptor enriched at developing joints.
[ Normal View | Magnified View ]
Iterative segmentation of the bony rays of the zebrafish fin. (a) The tail fin from a 1‐month‐old zebrafish was stained with alizarin red and alcian blue to highlight bone and cartilage, respectively. In the bony rays, a series of joints form in a segmental pattern from the base of the fin to the tip (left to right in this image). (b) Modeling predicts that just two morphogens can generate the segmental pattern of joints in the fin rays. Bone cells are shown in red, joint cells in black with blue nuclei, and progenitors in gray. At forming joints, one morphogen (green) specifies joint fates while inhibiting neighboring cells from becoming joints. At the distal end, a growth factor (red) drives progenitor growth (right arrow) that lengthens the fin while inhibiting joint formation. Over time (top to bottom), new joints form where both morphogens fall below a critical threshold. (c) The gap junction protein Connexin43, the potassium channel Kcnk5b, and the transcription factor Evx1 have all been shown to be required for correct joint spacing in the fin rays. One possibility is that secreted morphogens, as well as the transport of small molecules and electrical signaling between neighboring cells, combine to regulate joint spacing.
[ Normal View | Magnified View ]

Related Articles

Signaling and transcriptional regulation in neural crest specification and migration: lessons from xenopus embryos
How changes in fibril‐level organization correlate with the macrolevel behavior of articular cartilage (WIREs WIREs Systems Biology and Medicine)

Browse by Topic

Vertebrate Organogenesis > Musculoskeletal and Vascular
Signaling Pathways > Cell Fate Signaling
Gene Expression and Transcriptional Hierarchies > Cellular Differentiation