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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 (SEMD). In zebrafish, loss of function of ddrgk1 leads 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 knockout 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 that 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 the 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.

SUBMITTER: Weisz-Hubshman M

PROVIDER: S-EPMC9402238 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Weisz-Hubshman Monika M Egunsula Adetutu T AT Dawson Brian B Castellon Alexis A Jiang Ming-Ming MM Chen-Evenson Yuqing Y Zhiyin Yu Y Lee Brendan B Bae Yangjin Y

Human molecular genetics 20220801 16

Loss-of-function mutations in DDRGK1 have been shown to cause Shohat type spondyloepimetaphyseal dysplasia (SEMD). In zebrafish, loss of function of ddrgk1 leads 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 knockout mic ...[more]

PMID: 35377455

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Project description:BackgroundADAMTS aggrecanases play a major role in cartilage degeneration during degenerative and inflammatory arthritis. The cartilage-specific secreted protein Upper zone of growth plate and cartilage matrix associated protein (Ucma) has been shown to block ADAMTS-triggered aggrecanolysis in experimental osteoarthritis. Here we aimed to investigate whether and how Ucma may affect cartilage destruction and osteophyte formation in the context of inflammatory arthritis.MethodsUcma-ADAMTS5 protein interactions were studied using slot blot and solid phase binding assays. Chondrocyte cultures were stimulated with ADAMTS5 or IL-1β in the presence or absence of Ucma and aggrecanolysis was assessed by neoepitope formation. Arthritis was induced by transfer of K/BxN serum into wild-type (WT), Ucma-deficient and WT mice treated with recombinant Ucma. Cartilage proteoglycan loss and cartilage damage was assessed by safranin-O stain, aggrecanase-induced neoepitope formation and histomorphometry, respectively. Osteophytes were assessed by histomorphometry, micro-computed tomography, RNA in-situ hybridisation for collagen10a1 and osteocalcin, and staining for TRAP activity. Gene expression analyses were performed using real-time RT-PCR.ResultsUcma physically interacted with ADAMTS5 and blocked its aggrecanase activity in chondrocyte cultures. Ucma was highly expressed in the articular cartilage and in osteophytes during arthritis. Ucma had no effect on inflammation and bone erosion. In contrast, Ucma-deficient mice developed significantly more severe cartilage proteoglycan loss and cartilage destruction. Conversely, treatment with Ucma inhibited cartilage degeneration in arthritis. Ucma effectively inhibited ADAMTS5-triggered or IL-1β-triggered aggrecanolysis in vitro and in vivo. Furthermore, osteophyte formation was reduced in Ucma-deficient mice.ConclusionsThese results indicate that Ucma inhibits aggrecanolysis by physical interaction with ADAMTS5 and protects from cartilage degeneration in inflammatory arthritis. Ucma therefore represents an interesting novel and specific target for preventing cartilage degradation in the context of inflammatory arthritis.

Dataset Information

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

Publications

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

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