Lehmann Lab

​The role of adhesion G protein-coupled receptors in bone homeostasis

Our bones are not a rigid structure - even after they have completed their lengthening, they are in a constant process of building up, breaking down and remodeling. Various cell types such as osteoblasts, osteoclasts and osteocytes maintain bone homeostasis. While osteoblasts build bone, osteoclasts resorb bone tissue, both actions being tightly regulated by osteocytes. Many factors contribute to the regulation of their interaction and differentiation, thereby determining the relative rates of bone formation and resorption. The homeostasis of these processes is critical to prevent damage to bone structure and resultant metabolic bone disease. Research on aGPCRs is still in its infancy, but recent advances have highlighted a unique function for these receptors that combines GPCR- and integrin-like functions. There is increasing evidence that this class of receptors is important in bone development, homeostasis and disease. Which aGPCRs are expressed in osteoblasts, osteoclasts and osteocytes and how do they influence the differentiation and function of the individual bone cells? What role does the function of the aGPCR play as a mechanosensor and how does a loss of individual aGPCRs affect bone homeostasis in vivo? With the help of various in vitro and in vivo experiments, we want to get to the bottom of these questions.​

Validation of the repertoire and functional relevance of aGPCRs in osteoblasts osteoclasts and osteocytes

Although several aGPCRs have been implicated in bone disease or dysfunction, it remains unclear which of these receptors are involved in the regulation of bone homeostasis. By analyzing the expression pattern of all aGPCRs during differentiation of osteoblasts, osteoclasts and osteocytes, we have already identified a few promising candidates. With the help of a receptor-specific knockdown and the stimulation of the respective aGPCR with its agonistic peptide, we want to investigate the contribution of individual aGPCRs to the differentiation and function of bone cells and find out which signals are mediated by the respective receptor.

Phenotypic relevance of GPR133 in differentiation of osteoblasts and osteoclasts using a receptor-deficient mouse model

Initial investigations have already shown that Gpr133-KO mice have reduced bone mass. However, it is still unclear whether this phenotype results from decreased bone formation or increased bone resorption. To get to the bottom of this question, the bones of the animals are examined in more detail. Among other things, the microarchitecture is examined using µCT and its cellular structure is analyzed using histological methods. In addition, various serum parameters are examined.

Establishment of an in vitro stretching model for osteoblasts and osteocytes to investigate the role of GPR133 as a metabotropic mechanosensor

Mechanical stress has been shown to promote differentiation of osteoblasts while impeding differentiation into adipocytes. The duration and intensity of the mechanical stimulus plays a decisive role and influences the activation or inhibition of various signaling pathways involved in the differentiation process. Even though several aGPCRs have already been identified as potential mechanoreceptors, we initially focus on GPR133. For this purpose, an in vitro stretching model with primary cells has already been developed in our laboratory. With the help of further experiments we want to investigate the relevance of GPR133 as a mechanoreceptor in osteoblasts and osteocytes.​

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1. Lehmann J, Thiele S, Baschant U, Rachner TD, Niehrs C, Hofbauer LC, Rauner M. Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss. iScience. 2021;24(3):102224.
2. Hildebrandt N*, Colditz J*, Dutra C, Goes P, Salbach-Hirsch J, Thiele S, Hofbauer LC, Rauner M. Role of osteogenic Dickkopf-1 in bone remodeling and bone healing in mice with type I diabetes mellitus. Sci Rep 2021;11(1)1920. *Shared co-first authorship
3. Schütt J, Sandoval Bojorquez DI, Avitabile E, Oliveros Mata ES, Milyukov G, Colditz J, Delogu LG, Rauner M, Feldmann A, Koristka S, Middeke JM, Sockel K, Fassbender J, Bachmann M, Bornhäuser M, Cuniberti G, Baraban L. Nanocytometer for smart analysis of peripheral blood and acute myeloid leukemia: a pilot study. Nano Lett. 2020;20(9):6572-6581.
4. Colditz J*, Picke AK*, Hofbauer LC, Rauner M. Contributions of Dickkopf-1 to Obesity-Induced Bone Loss and Marrow Adiposity. JBMR Plus. 2020 Apr 28;4(6):e10364. *Shared co-first authorship
5. Colditz J, Thiele S, Baschant U, et al. Osteogenic Dkk1 Mediates Glucocorticoid-Induced but Not Arthritis-Induced Bone Loss. J Bone Miner Res. 2019;34(7):1314‐1323.
6. Tsourdi E*, Colditz J*, Lademann F, Rijntjes E, Köhrle J, Niehrs C, Hofbauer LC, Rauner M. The Role of Dickkopf-1 in Thyroid Hormone-Induced Changes of Bone Remodeling in Male Mice. Endocrinology. 2019;160(3):664‐674. doi:10.1210/en.2018-00998 *Shared co-first authorship
7. Colditz J, Thiele S, Baschant U, Niehrs C, Bonewald LF, Hofbauer LC, Rauner M. Postnatal Skeletal Deletion of Dickkopf-1 Increases Bone Formation and Bone Volume in Male and Female Mice, Despite Increased Sclerostin Expression. J Bone Miner Res. 2018;33(9):1698‐1707. 

02/2020 – present