Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica

Abstract

Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full knockout, Gorab was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only GorabPrx1 and GorabRunx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of GorabNull mutants and in bone of GorabPrx1 mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from GorabNull mutants. In bone from GorabPrx1 mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured GORAB-deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-β in GorabPrx1 bone tissue leading to enhanced downstream signalling, which was reproduced in GORAB-deficient fibroblasts. Our data suggest that the loss of Gorab primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.

Membrane trafficking in health and disease

“…Similarly, mutations in the trans-Golgi protein RAB6interacting golgin (GORAB), which functions in COPI-mediated traffic, cause the skin and bone disorder gerodermia osteodysplastica, likely as a consequence of disrupted matrix protein glycosylation (Hennies et al, 2008;Witkos et al, 2019). This not only affects matrix assembly, but is also important for controlling TGFβ (also known as TGFB1) signalling to prevent cell senescence (Chan et al, 2018). Mutations in Golgi RAB33B cause Smith-McCort syndrome (Dupuis et al, 2013), an osteochondrodysplasia.…”

From Translation to Protein Degradation as Mechanisms for Regulating Biological Functions: A Review on the SLRP Family in Skeletal Tissues

“…However, for decorin, its non-proteoglycan form is always a minor component, even though there is also an increase related to age [88]. In cortical bone, the level of decorin glycanation decreases with age [90]. Finally, the decorin GAG length is reduced in the tendon fascicle of old mice [91].…”

“…Defective glycanation is correlated with pathological states, for instance in gerodermia osteodysplastica. In the organism model corresponding to this pathology characterized by the early onset of osteoporosis, decorin and biglycan are glycanated to a lesser extent, and it is suggested that this defect is involved in the abnormal gain of periosteum thickness [90]. Equine degenerative suspensory ligament desmitis (DSLD), which affects tendons, ligaments, and other connective tissues and resembles Ehlers-Danlos syndrome, correlates with the accumulation of decorin carrying abnormally glycosylated GAG chains [105].…”

A conserved retromer-independent function for RAB-6.2/RAB6 inC. elegansepidermis integrity

“…The mechanism by which RAB-6.2 may regulate glycosylation is likely indirect, resulting from the role of RAB-6.2 in Golgi trafficking of client proteins and/or glycosylation enzymes like BUS-17 (Fisher and Ungar, 2016). Significantly, Golgi-related glycosylation defects are also linked to many inherited diseases, some of which affect the skin and bones, and mutations in RAB6-interacting proteins cause severe inherited diseases with strong skin defects such as gerodermia osteodysplastica and congenital disorders of glycosylation (CDG) in humans (Chan et al, 2018;Freeze and Ng, 2011;Hennies et al, 2008;Egerer et al, 2015;Wu et al, 2004;Sun et al, 2007).…”