Molecular profiling of synovial joints: Use of microarray analysis to identify factors that direct the development of the knee and elbow

Abstract

Background: Synovial joints develop from the interzone, a dense layer of mesenchymal progenitor cells that marks the site of the future joint. During the morphogenic events that follow, joints attain their distinct shape and organization. The molecular mechanisms controlling the initial specification of synovial joints has been studied, but the question of how individual joints attain the specific structure required for their unique functions remains largely unresolved. Here, we use microarray analysis to compare knee and elbow formation to identify factors involved in the development of specific joints. Results: The knee is enriched for the hindlimb patterning genes Hoxc9, Hoxc10, and Tbx4 and for Tgfbi, Rspo2, and Sfrp2, factors involved in transforming growth factor-beta/bone morphogenetic protein (TGFb/BMP) and Wnt signaling. Consistent with these findings, we show that TGFb signaling directs knee morphogenesis, and is necessary for meniscus development. The tissue surrounding the elbow is highly enriched for genes involved in muscle specification and differentiation, and in splotch-delayed muscleless mutants, elbow, but not knee morphogenesis is disrupted. Conclusions: Our results suggest there are fundamental differences in how individual joints develop after interzone formation. Our microarray analyses provides a new resource for further investigation of the pathways involved in the morphogenesis of specific synovial joints.

Genesis and morphogenesis of limb synovial joints and articular cartilage

“…These interesting findings raised the possibility that development of diverse limb joints may also involve differential responses to common cues such as muscle-driven movement. In a related and as interesting study, Pazin and collaborators carried out gene array-based molecular profiling to identify factors that direct the development of elbow and knee in mouse embryos (Pazin et al, 2012). They identified the period between E15 and E16 in which clear elbow- and knee-specific molecular identities could be uncovered.…”

Mouse limb skeletal growth and synovial joint development are coordinately enhanced by Kartogenin

“…Using Gdf5Cre mice to ablate floxed target genes, we and others showed that the behavior and function of interzone cells involve multiple mechanisms including Wnt/β-catenin signaling and cell surface/matrix macromolecule interactions (Koyama et al, 2008; Mundy et al, 2011). Recent studies have shown that joint formation also requires skeletal muscle function and contraction and signaling by β-catenin (Kahn et al, 2009; Pazin et al, 2012). The increasing research attention surrounding joint formation reflects the fact that many aspects of it remain stubbornly unclear and difficult to decipher, and that a much better understanding in this area could lead to the conception and creation of regenerative and repair tools for common and currently unsolved joint pathologies, including osteoarthritis (OA), severe joint injury, and congenital joint dysplasias (Onyekwelu et al, 2009; Sandell, 2012; Umlauf et al, 2010).…”

Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions

“…Formation of joint-specific structures during embryogenesis is accompanied by tightly controlled topographical and temporal expression of specific sets of positional genes, including homeobox (HOX) transcription factors1. The highly conserved HOX transcription factors specify regional identities of cells and tissues throughout the body and regulate the correct formation of the body axes23.…”