Identification of osteoclast endocrine and paracrine communications by systems genetics approaches

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Bone resorption by osteoclasts plays a pivotal role in skeleton growth, homeostasis, and fracture repair. In adults, bone health is ensured by bone remodeling in which bone resorption is coupled and balanced by bone formation from osteoblasts. Therefore, the number and activities of osteoclasts are tightly regulated by systemic hormones and paracrine factors in bone marrow microenvironment. Meanwhile, bone itself is increasingly recognized as an endocrine organ which can modulate functions of other organs in whole-body physiology. While the systemic functions of endocrine factors derived from osteoblasts and osteocytes such as FGF23 and osteocalcin have been well established, the endocrine functions of osteoclast secreted proteins remain to be uncovered. To identify and functionally annotate endocrine and paracrine circuits, we have developed a novel systems genetic approach, termed Quantitative Endocrine Network Interaction Estimation (QENIE), that utilizes natural variation in transcript levels across tissues in multiple ‘omics’ datasets to predict modes of endocrine communication. Applying this approach to datasets in the hybrid mouse diversity panel (HMDP), a collection of approximately 100 inbred strains of mice exhibiting substantial diversity of most clinical traits relevant to human diseases, we have unraveled many known endocrine interactions as well as several novel tissue-tissue circuits. In the preliminary study leading to this proposal, we have quantitatively measured the levels of proteins and RNAs in precursor and mature osteoclasts by mass-spectrometry based proteomic and bulk RNA-seq. Hundreds of secreted proteins in osteoclast lineage cells have been identified by these ‘omics’ studies. While several osteoclast-derived coupling factors known to stimulate osteogenesis during bone remodeling are in the list of osteoclast secreted proteins, the endocrine and paracrine functions of most of these newly identified osteoclast secretory proteins are unknown. Based on our work and reports by others, we hypothesize that the endocrine and paracrine communications of osteoclasts play an important role in whole body and bone homeostasis under physiological and pathological conditions. To test our hypothesis, we will identify novel endocrine and paracrine circuits of osteoclast lineage cells by the system genetics bioinformatic framework QENIE (Aim 1) and experimentally validate and functionally assess these osteoclast-derived factors by in vitro cell culture and co-culture models (Aim 2). Successful accomplishment of the proposed work in this application will formulate new hypotheses to be tested using in vivo animal models and in human populations. The findings from this project will not only greatly advance our knowledge in osteoclast biology but also uncover new therapeutic targets to treat bone loss in bone and other organ diseases.