03 Apr Gene Expression Links Gastric Absorption and Bone Mass
MedicalResearch.com Interview with:
Ricardo Battaglino, Ph.D.
Department of Mineralized Tissue Biology
The Forsyth Institute, Cambridge, Massachusetts
Department of Oral Medicine, Infection, and Immunity
Harvard School of Dental Medicine,
Boston, Massachusetts
Medical Research: What is the background for this study? What are the main findings?
Dr. Battaglino: Mutations in sorting nexin 10 (Snx10) have recently been found to account for roughly 4% of all human malignant osteopetrosis, some of them fatal. To study the disease pathogenesis, we investigated the expression of Snx10 and created mouse models in which Snx10 was knocked down globally or knocked out in osteoclasts. We found that Snx10, a molecule expressed in osteoclasts, was also expressed in the stomach. Studies in tissue specific or global knock-down mice showed that Snx10 deficiency resulted in a phenotype that was a consequence of deficiencies in both osteoclasts and gastric zymogenic cells. Our studies add to a growing list of genes, including atp6i (Tcirg1), whose expression is required both in bone and stomach to maintain normal gastric acidification and calcium absorption.
Medical Research: What should clinicians and patients take away from your report?
Dr. Battaglino: Our work provides additional insight into the mechanisms governing the regulation of bone accrual by the gastrointestinal tract. Because osteopetrorickets has not been described clinically in Snx10-related osteopetrosis, these findings highlight the importance of considering impaired acidification in both stomach and bone in osteopetrotic patients with mutations in SNX10 and other genes with similar patterns of expression and activities. Reliance solely on hematopoietic stem cell transplantation can leave hypocalcemia uncorrected with sometimes fatal consequences. Because defects in gastric differentiation and/or gastric acidification may cause or contribute to hypocalcemia, bone insufficiency, and early death, our results suggest that dietary calcium supplementation could be a life-saving intervention in these patients.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Battaglino: The skeleton is one of the largest tissues of the vertebrate body plan and as such cannot function in isolation. Instead, there is a complex system of cross-regulation that exists between bone and most other organs. The ability to perform tissue or cell-specific gene ablation has afforded us the experimental tools to understand how organs signal to one another and has revitalized the concept of whole-organism physiology. The regulation of bone mass by the gastrointestinal tract represents a remarkable example of an unexpected and novel relationship between these two systems that is only now becoming fully appreciated. Our work is expected to elucidate the role of SNX10 in early endosomal formation and subsequent OC function. In addition, we anticipate that expression of Snx10 in stomach regulates calcium bioavailability by controlling gastric pH.
This work will lay the foundation for future studies that may address the following questions:
1) can we use analysis of expression patterns of gene networks across systems to identify novel regulatory functions between bone and gut (and/or other systems) and
2) does Snx10 partner with different proteins in OCs and stomach? This all may be important for the development of therapies that preferentially target Snx10 in OCs but not stomach.
Citation:
PLoS Genet. 2015 Mar 26;11(3):e1005057. doi: 10.1371/journal.pgen.1005057. eCollection 2015.
Ye L1, Morse LR2, Zhang L3, Sasaki H4, Mills JC5, Odgren PR6, Sibbel G5, Stanley JR7, Wong G7, Zamarioli A8, Battaglino RA1.
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MedicalResearch.com Interview with: Ricardo Battaglino, Ph.D. (2015). Gene Expression Links Gastric Absorption and Bone Mass
Last Updated on April 3, 2015 by Marie Benz MD FAAD