Karl Insogna, MD, FACP

Dr. Insogna maintains active programs in both clinical and bench research.

In the clinical arena, Dr. Insogna is interested in the role of dietary protein in skeletal metabolism. Over the past decade, he and Dr. Jane Kerstetter from the University of Connecticut have established a new paradigm for the effect of dietary protein on calcium homeostasis. They have found that, contrary to the widely held view, increases in dietary protein within the physiologic range do not result in negative bone balance. Using dual stable calcium isotopes, they determined that the long-recognized hypercalciuria, which attends an increase in dietary protein, is quantitatively explained by improved intestinal calcium absorption, rather than increased bone resorption. In fact, the rate of resorption tends to slow as dietary protein is increased from low to high-normal. These data have led Drs. Insogna, Kerstetter, and Anne Kenney (from the University of Connecticut) to launch an NIH-funded, multi-center trial examining the impact of a dietary protein supplement on bone metabolism in postmenopausal women. Ongoing studies also seek to better define the cellular and molecular mechanisms by which dietary protein augments intestinal calcium absorption. Some of this work suggests a potential role for the calcium-sensing receptor, but alternative theories are currently being explored in the laboratory.

Another area of active clinical investigation involves understanding the factors that lead to skeletal disease in adult patients with X-linked hypophosphatemic rickets. Research over the last decade has improved our understanding of the pathogenesis of hypophosphatemic disorders, and this new information is being applied in two clinical trials currently being conducted by Dr. Insogna and Dr. Thomas Carpenter from the Department of Pediatrics. These studies seek to determine the clinical and biochemical factors that lead to skeletal complications, such as enthesopathy and spinal ligament calcification, in this disease. Finally, Dr. Insogna and Dr. M. Tish Knobf from the School of Nursing are beginning an NIH-funded study to examine the impact of exercise on bone health in postmenopausal breast cancer survivors.

In the laboratory, Dr. Insogna’s interest focuses on cellular mechanisms of PTH-induced bone resorption and bone anabolism. He has had a long-standing interest in the role of interleukin-6 in mediating PTH-induced bone resorption. Current efforts in that area focus on the role of IL-6 in PTH-induced RANK ligand expression. Another major research effort in the laboratory is to define the role of the two Colony Stimulating Factor-1 (CSF1) isoforms in bone. Work from the Insogna laboratory has established that CSF1 is the major colony-stimulating factor released by osteoblasts in response to PTH. Further work supports the hypothesis that the soluble and membrane CSF1 isoforms serve non-redundant roles in bone. Selective deletion of each isoform in vivo is being pursued to better define their separate roles. As an example, we are currently examining the possibility that sCSF-1 has a unique role in estrogen-deficiency bone loss.

The laboratory is also interested in the effects of CSF1 in mature osteoclasts. CSF-1 is an important chemoattractant in vivo for osteoclasts, and the laboratory is exploring the molecular mechanisms by which CSF-1 induces cytoskeletal remodeling and osteoclast motility. The downstream targets for CSF1 in osteoclasts include PI 3-kinase, Rac1, LIM kinase 1, and cofilin. In the course of this work, the laboratory has identified unique interacting proteins that partner with Rac1, including BCA3, (Breast Cancer Associated Protein 3). The role of BCA3 is incompletely understood but one function appears to be a nuclear/cytoplasmic shuttle. This finding, in conjunction with an emerging nuclear role Rac1 suggests novel, hitherto unappreciated nuclear functions for Rac1 in osteoclasts. There is an ongoing interest in the laboratory in identifying environmental and genetic modifiers of PTH’s anabolic actions, which has lead to studies exploring the modulating effects of aging, diet and genes that regulate osteoclast function. Finally, the laboratory is interested in Wnt signaling and its role in lineage allocation in bone. Our current interest is in identifying Wnt-dependent metabolic pathways that regulate mesenchymal stem cell differentiation towards the osteoblast lineage and away from an adipocyte fate. For more information on Dr. Insogna's bench and clinical research, please visit https://medicine.yale.edu/lab/insogna.