Role of TGF-β in a Mouse Model of High Turnover Renal Osteodystrophy

Abstract

Altered bone turnover is a key pathologic feature of chronic kidney disease-mineral and bone disorder (CKD-MBD). Expression of TGF-β1, a known regulator of bone turnover, is increased in bone biopsies from individuals with CKD. Similarly, TGF-β1 mRNA and downstream signaling is increased in bones from jck mice, a model of high-turnover renal osteodystropy. A neutralizing anti-TGF-β antibody (1D11) was used to explore TGF-βs role in renal osteodystrophy. 1D11 administration to jck significantly attenuated elevated serum osteocalcin and type I collagen C-telopeptides. Histomorphometric analysis indicated that 1D11 administration increased bone volume and suppressed the elevated bone turnover in a dose-dependent manner. These effects were associated with reductions in osteoblast and osteoclast surface areas. μCT confirmed the observed increase in trabecular bone volume and demonstrated improvements in trabecular architecture and increased cortical thickness. 1D11 administration was associated with significant reductions in expression of osteoblast marker genes (Runx2, alkaline phosphatase, osteocalcin) and the osteoclast marker gene, Trap5. Importantly, in this model, 1D11 did not improve kidney function or reduce serum PTH levels indicating that 1D11 effects on bone are independent of changes in renal or parathyroid function. 1D11 also significantly attenuated high turnover bone disease in the adenine-induced uremic rat model. Antibody administration was associated with a reduction in pSMAD2/SMAD2 in bone but not bone marrow as assessed by quantitative immunoblot analysis. Immunostaining revealed pSMAD staining in osteoblasts and osteocytes but not osteoclasts, suggesting 1D11 effects on osteoclasts may be indirect. Immunoblot and whole genome mRNA expression analysis confirmed our previous observation that repression of Wnt/β catenin expression in bone is correlated with increased osteoclast activity in jck mice and bone biopsies from CKD patients. Furthermore, our data suggests that elevated TGF-β may contribute to the pathogenesis of high turnover disease partially through inhibition of β-catenin signaling.

Bone remodeling markers and bone metastases: From cancer research to clinical implications

“…[31][32][33][34][35][36][37][38][39][40][41] In addition, in nonhuman primate models, serum markers of bone resorption were also consistent with the observed phenotype. [42][43][44][45][46] Biomarkers of bone remodeling can also be used in in vitro models.…”

The Relationship Between Inflammatory Biomarkers and Symptom Distress in Lung Cancer Patients Undergoing Chemotherapy

“…According to the relationship between symptom distress and TRACP5a (Table 4), we further expected that a potential inhibitor of TRACP5a could efficiently contribute to relieve the fatigue, overcome the sleep disturbance, alleviate the pain, treat the depression, and clear the confusion. Because TRACP5a, which generally belongs to the TRACP family, also expresses in osteoclasts as an osteoclast biomarker gene, 29 several researchers have recently demonstrated that TRACP can be reduced by some drugs, such as GF109203X, 52 receptor activator of the nuclear factor .B ligand (RANKL) inhibitors, 53 and tacrolimus, 54 to attenuate osteoclastogenesis. In addition, RANKL induced monocyte/macrophage cells for osteoclastic differentiation 55 and generation of TRACP-positive multinucleated cells in bone marrowYderived monocytes.…”

“…26Y28 It has been suggested that TRACP5a is an osteoclast biomarker gene. 29 Studies have revealed that TRACP5a is a possible reflection of disease severity associated with mounting numbers of systemic inflammatory macrophages. 30,31 In contrast, serum TRACP5b is a proteolytically cleaved form with disulfide-linked polypeptide subunits of 16 and 23 kDa, which has no sialic acid in its oligosaccharides.…”

Osteoclasts—Key Players in Skeletal Health and Disease

“…Furthermore, the effects of TGF-β or its inhibition in disease settings is complicated by the universality of TGF-β receptor expression. For bone, osteoblasts also mount physiologically relevant responses to TGF-β, and these may be dominant to the effects on OC, for example in renal osteodystrophy (240). In this study, TGF-β neutralization limited downstream signaling in osteoblasts and osteocytes, but not in OC.…”