Abstract:The articular cartilage, which lines the joints of the limb skeleton, is distinct from the adjoining transient cartilage, and yet, it differentiates as a unique population within a contiguous cartilage element. Current literature suggests that articular cartilage and transient cartilage originate from different cell populations. Using a combination of lineage tracing and pulse-chase of actively proliferating chondrocytes, we here demonstrate that, similar to transient cartilage, embryonic articular cartilage c… Show more
“…Moreover, decreased TGFβR2 signaling in the joint region has been shown to impair chondrocyte hypertrophy at embryonic stages via increased expression of the cytokine MCP5 (Longobardi et al, 2012), but we were not able to detect MCP5 mRNA or protein in our model at P3. On the other hand, RNA and protein levels of the WNT target Lef1 were upregulated in the RZ of the left P1-Pit::DTR GP compared to right (Figure 3C; see also Figure 4—figure supplement 2, n = 5 at P3, 4 at P4, 3 at P5), which might impair PTHLH signaling and chondrocyte differentiation, as described (Ray et al, 2015; Guo et al, 2009). In summary, our results show that damage in the tissues adjacent to the early postnatal GPs results in alterations in multiple GP signaling pathways known to regulate bone growth.10.7554/eLife.27210.007Figure 3.Multiple signaling pathways related to chondrocyte proliferation and maturation are altered in distinct regions of the left P1-Pit::DTR growth plate.( A–A’ ) In situ hybridization for Ihh and the HH target Gli1 , in the left and right proximal tibia of Pit::DTR mice, 2dpi.…”
Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as an internal control. Remarkably, when only mesenchyme cells surrounding postnatal GPs were killed, left bone growth was nevertheless reduced. GP signaling was impaired by altered paracrine signals from the knee joint, including activation of the injury response and, in neonates, dampened IGF1 production. Importantly, only the combined prevention of both responses rescued neonatal growth. Thus, we identified signals from the knee joint that modulate bone growth and could underlie establishment of body proportions.DOI:
http://dx.doi.org/10.7554/eLife.27210.001
“…Moreover, decreased TGFβR2 signaling in the joint region has been shown to impair chondrocyte hypertrophy at embryonic stages via increased expression of the cytokine MCP5 (Longobardi et al, 2012), but we were not able to detect MCP5 mRNA or protein in our model at P3. On the other hand, RNA and protein levels of the WNT target Lef1 were upregulated in the RZ of the left P1-Pit::DTR GP compared to right (Figure 3C; see also Figure 4—figure supplement 2, n = 5 at P3, 4 at P4, 3 at P5), which might impair PTHLH signaling and chondrocyte differentiation, as described (Ray et al, 2015; Guo et al, 2009). In summary, our results show that damage in the tissues adjacent to the early postnatal GPs results in alterations in multiple GP signaling pathways known to regulate bone growth.10.7554/eLife.27210.007Figure 3.Multiple signaling pathways related to chondrocyte proliferation and maturation are altered in distinct regions of the left P1-Pit::DTR growth plate.( A–A’ ) In situ hybridization for Ihh and the HH target Gli1 , in the left and right proximal tibia of Pit::DTR mice, 2dpi.…”
Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as an internal control. Remarkably, when only mesenchyme cells surrounding postnatal GPs were killed, left bone growth was nevertheless reduced. GP signaling was impaired by altered paracrine signals from the knee joint, including activation of the injury response and, in neonates, dampened IGF1 production. Importantly, only the combined prevention of both responses rescued neonatal growth. Thus, we identified signals from the knee joint that modulate bone growth and could underlie establishment of body proportions.DOI:
http://dx.doi.org/10.7554/eLife.27210.001
“…Recent evidence indicates that a continuous influx of GDF5 (growth differentiation factor 5) positive cells contributes to joint development (Ray et al ., 2015; Shwartz et al ., 2016). With the upregulation of unique molecules such as Wnt9A (Wingless-Type MMTV Integration Site Family, Member 9A), GDF5, Erg (ets related gene), Gli3 (GLI Family Zinc Finger 3), CD44 (cluster differentiation 44), and type IIA/I collagen (Iwamoto et al , 2007; Koyama et al , 2008; Pacifici et al , 2006), cavitation appears within the interzone (Archer et al , 2003).…”
Section: Vascular Neural and Basic Anatomymentioning
The degradation of cartilage in the human body is impacted by aging, disease, genetic predisposition, and continued insults resulting from daily activity. The burden of cartilage defects (osteoarthritis, rheumatoid arthritis, intervertebral disc damage, knee replacement surgeries, etc.) is daunting in light of substantial economic and social stresses. This review strives to broaden the scope of regenerative medicine and tissue engineering approaches used for cartilage repair by comparing and contrasting the anatomical and functional nature of the meniscus, articular cartilage (AC), and nucleus pulposus (NP). Many review papers have provided detailed evaluations of these cartilages and cartilage-like tissues individually, but none have comprehensively examined the parallels and inconsistencies in signaling, genetic expression, and extracellular matrix (ECM) composition between tissues. For the first time, this review outlines the importance of understanding these three tissues as unique entities, providing a comparative analysis of anatomy, ultrastructure, biochemistry, and function for each tissue. This novel approach highlights the similarities and differences between tissues, progressing research toward an understanding of what defines each tissue as distinctive. The goal of this paper is to provide researchers with the fundamental knowledge to correctly engineer the meniscus, AC, and NP without inadvertently developing the wrong tissue function or biochemistry.
“…That this Bmp activity originates in the interdigit has been shown genetically in the mouse (Huang et al, 2016), where it is modulated through Hoxd-Gli3 antaganism. Moreover, GDF5, a divergent member of the Bmp superfamily, is a very early marker of the non-chondrogenic future joint cells (Ray et al 2015), and has been shown to induce chondrogenesis both in vitro and in vivo (Francis-West et al, 1999; Storm and Kingsley, 1949). Wnt activity is also present in the non-chondrogenic interdigit domains.…”
Section: Integrating Joint Formation Into the Picturementioning
Critical steps in forming the vertebrate limb include the positioning of digits and the positioning of joints within each digit. Recent studies have proposed that the iterative series of digits is established by a Turing-like mechanism generating stripes of chondrogenic domains. However, reexamination of available data suggest digits are actually patterned as evenly spaced spots, not stripes, that then elongate into rod-shaped digit rays by incorporating new cells at their tip. Moreover, extension of the digit rays and the patterning of the joints occur simultaneously at the distal tip, implying an integrated model is required to fully understand these processes.
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