Project Details
Projekt
Molecular analysis of the bidirectional crosstalk between bone and lipid metabolism
Applicant
Professor Dr. Jörg Heeren
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517063424
Several osteoblast-secreted factors have paracrine and/or endocrine properties that are critical for local bone metabolism and in part even for systemic energy metabolism. Next to proteins and peptides, hydrophilic and lipophilic metabolites have emerged as signaling molecules that actively participate in multiple metabolic processes. Within the clinical research group ProBone (“Precision Medicine for Early-Onset Low Bone Mineral Density Disorders”), the overall goal of P6 is to define changes in osteoblast-derived hydrophilic and lipophilic metabolites that are altered in patients with early-onset low bone mineral density (BMD). The focus will be on metabolites with potential signaling properties that may influence molecular pathways controlling skeletal integrity and/or systemic metabolism. In collaboration with P1, P4, P5 and CP1, we will define lipidomic and metabolomic signatures of human and mouse osteoblasts, which express wild type and variants of skeletal disease genes. Specifically, together with P1 and P4 we aim to determine the role of the early onset low BMD genes IFITM5 and SMS for metabolite and lipid signatures. In addition, we will collaborate with P1 and P5 to study osteoblasts lacking functional protein expression of TNSALP and ENPP1, which are important enzymes affecting the stepwise conversion of ATP to adenosine. Based on clinical studies performed by P1, P2 and CP1 and with the help of bioinformatic approaches for comparative metabolite analysis provided by CP2, we will select the most promising metabolite candidates. These will be investigated regarding their potential anti-osteoanabolic properties that may influence differentiation and function of murine and human osteoblasts and/or osteoclasts. Additionally, to achieve disease stratification and gain a better understanding of patient-specific pathologies, P6 aims to define metabolite and lipid profiles associated with early-onset low BMD disorders in human serum samples by mass spectrometry-based approaches. In collaboration with P1, P7, P8 and CP2, this may lead to the identification of so far unknown secondary causes of early-onset low BMD, which may be triggered by bioactive metabolites or activation of specific immune cell populations. To directly assess the potential impact on systemic metabolism, we are collaborating with P4 and P5 to perform deep metabolic phenotyping for the quantification of energy expenditure, locomotor activity and fuel selection at the whole-body level in selected mouse models. Overall, the results of P6 may lead to the identification of novel osteoanabolic molecules and/or signaling pathways. Moreover, our findings may contribute to the molecular understanding of pathogenic variants and may pinpoint towards non-genetic causes of early onset low BMD disorders.
DFG Programme
Clinical Research Units
