Chondrocytic Atf4 regulates osteoblast differentiation and function via Ihh

Abstract

SUMMARYAtf4 is a leucine zipper-containing transcription factor that activates osteocalcin (Ocn) in osteoblasts and indian hedgehog (Ihh) ;Col2a1-Atf4, but not Atf4 -/-cartilage, corrects the differentiation defects of Atf4 -/-bone marrow stromal cells and Ihh-blocking antibody eliminates this effect. Together, these data indicate that Atf4 in chondrocytes is required for normal Ihh expression and for its paracrine effect on osteoblast differentiation. Therefore, the cell-autonomous role of Atf4 in chondrocytes dominates the role of Atf4 in osteoblasts during development for the control of early osteogenesis and skeletal growth.

Overexpression of TIMP-3 in Chondrocytes Produces Transient Reduction in Growth Plate Length but Permanently Reduces Adult Bone Quality and Quantity

“…Unsurprisingly, chondrocyte-selective deletion of collagen type II resulted in smaller mice with shorter bones and thinner trabeculae [25]. Interestingly, a recent paper describes the role of chondrocyte-specific ATF4 (Activating Transcription Factor 4) in bone development and architecture [26]. Akin to our findings, the authors showed that chondrocyte-selective ATF4 deficiency (as opposed to TIMP3 overexpression) also delayed formation of ossification centers, resulted in short bones and also decreased bone mass and osteoblast differentiation; which were all rescued by cartilage-selective ATF4 overexpression.…”

“…In addition, it has been suggested that such crosstalk via the transfer of proteins can also occur between articular cartilage and subchondral bone in osteoarthritic joints in vivo [28]. It has also been shown that Ihh and other factors secreted by cartilage can affect osteoblast differentiation and that fibroblast growth factors, BMPs and Wnts might also contribute similarly to this crosstalk [26, 29]. This supports the possibility that TIMP3 expressed by chondrocytes may act on osteoblasts and bone via a paracrine route.…”

Oxidative Stress, Unfolded Protein Response, and Apoptosis in Developmental Toxicity

“…Similarly, BMP2 also induced mild ER stress through the PERK/ATF4 pathway in osteogenesis (Saito et al, 2011). Alternatively, ATF4 may modulate osteogenesis through RSK2 (Ribosomal S6 protein kinase 2) (Yang et al, 2004) or regulate growth plate chondrocyte proliferation and differentiation as a transcription factor of Indian hedgehog, a factor required for skeletal development (Wang et al, 2012a). …”

“…ATF4 has been shown to play a role in physiological chondrocyte differentiation (Wang et al, 2012a); alteration of that pathway could result in toxicity to chondrocytes. For example, the UPR was induced in zebrafish displaying spinal curvature following treatment with silver nanoparticles (Christen et al, 2013).…”

Functional analyses reveal the essential role of SOX6 and RUNX2 in the communication of chondrocyte and osteoblast

“…Cartilage is not only a precursor of bone but is also an active participant in bone formation, as it secretes local cytokines coupling chondrogenesis and osteogenesis together [3][4][5]. It has been demonstrated that chondrocyte-derived Ihh regulates osteoblast differentiation and function [6,7]. Mice lacking parathyroid hormone (PTH)-related peptide (PTHrP) gene or its receptor, PTH/ PTHrP receptor (PPR), exhibited accelerated hypertrophy of chondrocyte, as well as stimulation of osteoblast differentiation [8,9].…”