DDRGK1 is required for the proper development and maintenance of the growth plate cartilage

Abstract

Loss-of-function mutations in DDRGK1 have been shown to cause Shohat type spondyloepimetaphyseal dysplasia. In zebrafish, loss-of-function of ddrgk1 lead to defects in early cartilage development. Ddrgk1−/− mice show delayed mesenchymal condensation in the limb buds and early embryonic lethality. Mechanistically, Ddrgk1 interacts with Sox9 and reduces ubiquitin mediated proteasomal degradation of Sox9 protein. To investigate the cartilage-specific role of DDRGK1, conditional knock-out mice were generated by intercrossing Prx1-Cre transgenic mice with Ddrgkfl/fl mice to delete its expression in limb mesenchymal cells. Mutant mice showed progressive severe shortening of the limbs and joint abnormalities. The growth plate showed disorganization with shortened proliferative zone and enlarged hypertrophic zone. In correlation with these findings Sox9 and Col2a1 protein levels were decreased while Col10a1 expression was expanded. These data demonstrate the importance of Ddrgk1 during growth plate development. In contrast, deletion of Ddrgk1 with the osteoblast-specific Osteocalcin-Cre and Leptin receptor-Cre lines did not show bone phenotypes suggesting the effect on limb development is cartilage-specific. To evaluate the role of DDRGK1 in cartilage postnatal homeostasis, inducible Agc1-CreERT2; Ddrgklfl/fl mice were generated. Mice in which Ddrgk1 was deleted at 3 months of age showed disorganized growth plate, with significant reduction in proteoglycan deposition. These data demonstrate a postnatal requirement for Ddrgk1 in maintaining normal growth plate morphology. Together, these findings highlight the physiological role of Ddrgk1 in development and maintenance of the growth plate cartilage. Furthermore, these genetic mouse models recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD.

Loss of DDRGK1 impairs IRE1α UFMylation in spondyloepiphyseal dysplasia

“…Although the initial stages of the unfolded protein response (UPR) are cytoprotective mechanisms that restore ER homeostasis, chronic activation of the UPR can result in apoptosis 22 , 23 . These studies strongly suggested that decreased DDRGK1-induced ER stress might be one of the mechanisms causing impaired chondrogenesis in the growth plate cells of Ddrgk1 -conditional knockout (cKO) mice 13 . Therefore, in this study, we aimed to elucidate the contribution of DDRGK1-mediated ER stress to SEMD.…”

“…Importantly, Adetutu et al previously reported that the loss of DDRGK1 in zebrafish led to the reduced expression of the cartilage-specific protein SRY-box transcription factor 9 (SOX9), causing chondrogenic disorders [5]. Furthermore, this group suggested that the same mechanism involved in the loss of DDRGK1 impaired the expression of Ivyspring International Publisher SOX9 and chondrogenesis in growth plate cells of Ddrgk1 fl/fl , Prx.1 Cre and Ddrgk1 fl/fl , Aggrecan-ERT Cre mice, causing an abnormally increased HZ [13].…”

The Post-Translational Role of UFMylation in Physiology and Disease

“…Therefore, UfBP1 defects lead to skeletal dysplasia by disturbing the SOX9-COL2A1 axis [89]. In addition, transgenic mice with conditionally UfBP1-depleted limb mesenchymal cells exhibited limb shortening and joint abnormalities, indicating that UfBP1 helps to mediate normal cartilage growth and development [91].…”

Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress

“…Ufmylation on UFBP1 promotes the stability of IRE1α [ 32 ], as well as the ER development [ 29 ] and ER-autophagy [ 45 ], all of these maintain the ER homeostasis. Additionally, UFBP1 is involved in various diseases, including cancers [ 42 , 46 , 47 ], skeletal dysplasia [ 48 , 49 ], anemia [ 38 , 39 ] and diabetes [ 24 ].…”