TGF-β signaling inhibits osteoanabolic response to PTH in Osteogenesis Imperfecta

• Applicant: Dr. Ingo Alexander Grafe
• Subject Area: Endocrinology, Diabetology, Metabolism ; Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 434125426

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by low bone mass, impaired mechanical bone strength and fractures. Additionally, OI bone exhibits an increased density of osteocytes, cells that reside within lacunae within the mineralized bone matrix and control bone remodeling. Interestingly, also the lacuna morphology is altered in OI bone, suggesting abnormal osteocyte function. Most OI cases are caused by autosomal dominant mutations in the genes encoding type I collagen. Recessive OI can be caused by mutations in genes that are involved in post-translational collagen modifications. Previously, we found that increased TGF-β signaling is an important contributor to the OI phenotype in mouse models of both dominant and recessive moderate/severe OI, and TGF-β inhibition improved bone mass and strength, and normalized osteocyte density. Intermittent PTH increases bone mineral density in patients with osteoporosis and mild OI, but is not effective in patients with more severe forms of OI. The reasons for this resistance to PTH treatment in moderate/severe OI are not known. Interestingly, the TGF-β and PTH signaling pathways interact to modulate bone remodeling and both pathways are involved in osteocyte function. We hypothesize that (I) increased TGF-β signaling in OI is a mechanisms that impairs the response to PTH treatment, (II) that TGF-β inhibition restores responsiveness to the osteoanabolic effects of PTH, and (III) that combined anti-TGF-β/PTH treatment improves bone mass and strength as well as the osteocyte phenotype in OI. To test these hypotheses, we will (i) determine to what extent TGF-β-inhibition restores the response to PTH treatment on bone quantity and quality in mouse models of dominant and recessive OI, (ii) characterize the molecular changes in the PTH signaling pathway and the interactions with TGF-β signaling ex vivo and in vitro, and (iii) determine the effects of anti-TGF-β/PTH treatment on the morphological and molecular osteocyte phenotype. This project will provide novel insights into the interactions between dysregulated TGF-β and PTH signaling as a mechanism of OI, and potentially lead to better treatment options for OI patients.

• DFG Programme: Research Grants