Synovial joint morphogenesis requires the chondrogenic action of Sox5 and Sox6 in growth plate and articular cartilage

Abstract

The mechanisms underlying synovial joint development remain poorly understood. Here we use complete and cell-specific gene inactivation to identify the roles of the redundant chondrogenic transcription factors Sox5 and Sox6 in this process. We show that joint development aborts early in complete mutants (Sox5−/−6−/−). Gdf5 and Wnt9a expression is punctual in articular progenitor cells, but Sox9 downregulation and cell condensation in joint interzones are late. Joint cell differentiation is unsuccessful, regardless of lineage, and cavitation fails. Sox5 and Sox6 restricted expression to chondrocytes in wild-type embryos and continued Erg expression and weak Ihh expression in Sox5−/−6−/− growth plates suggest that growth plate failure contribute to this Sox5−/−6−/− joint morphogenesis block. Sox5/6 inactivation in specified joint cells and chondrocytes (Sox5fl/fl6fl/flCol2Cre) also results in a joint morphogenesis block, whereas Sox5/6 inactivation in specified joint cells only (Sox5fl/fl6fl/flGdf5Cre) results in milder joint defects and normal growth plates. Sox5fl/fl6fl/flGdf5Cre articular chondrocytes remain undifferentiated, as shown by continued Gdf5 expression and pancartilaginous gene downregulation. Along with Prg4 downregulation, these defects likely account for joint tissue overgrowth and incomplete cavitation in adult mice. Together, these data suggest that synovial joint morphogenesis relies on essential roles for Sox5/6 in promoting both growth plate and articular chondrocyte differentiation.

Mesenchyme-specific Knockout of ESET Histone Methyltransferase Causes Ectopic Hypertrophy and Terminal Differentiation of Articular Chondrocytes

“…To further confirm that formation of articular chondrocytes is not affected by ESET knock-out during joint development, we examined expression of ERG, an ETS family transcription factor whose mRNA has been reported to accumulate at the forming synovial joint but absent from growth plate cartilage (10,11). As shown in Fig.…”

Musculoskeletal integration at the wrist underlies modular development of limb tendons

“…Since other tendons were largely unaffected, whereas skeletal development was severely affected, these results suggest that Ihh and Sox5/6 do not play direct molecular roles in tendon differentiation, but that secondary signals from the skeleton might regulate FDS tendon development. Interestingly, although the skeletal phenotypes of these mutants are significantly different, a phenotypic feature common to both mutants is the loss of all phalangeal joints (Dy et al, 2010;St-Jacques et al, 1999). The possibility that induction of the FDS digit segment is dependent on cues from the forming joint is further supported by the fact that formation of the MP joint is concurrent with the initial stages of FDS digit tendon induction (Li et al, 2010).…”

MicroRNA-140 and the silencing of osteoarthritis

“…Therefore, the integration of endochondral bone development and joint development in the digits results in a functional synovial articulation: two bones whose articular surfaces are covered with articular cartilage, separated by a synovial fluid-filled point cavity, and connected by the joint capsule. Soluble proteins such as GDF5, Wnt14, and Noggin, and transcription factors such as Sox5, Sox 6, and Hif-1a are the main regulators of joint development (Brunet et al 1998;Storm and Kingsley 1999;Hartmann and Tabin 2001;Provot et al 2007;Dy et al 2010). However, it is still largely unclear how these different signals are integrated to form articular joints.…”