Osteoporosis remains a major cause of morbidity and mortality. Parathyroid hormone (PTH) is the only currently available therapy that substantially increases bone mass, but this therapy's effectiveness wanes with time. Our lack of understanding of the limitations of PTH therapy reflects very incomplete understanding of why PTH increases bone mass. We need to understand better the cellular targets of PTH and the intracellular mediators of PTH action. We propose to clarify both the cellular targets of PTH action and to identify a previously missed link in the action of PTH on osteocytes.
In Aim 1, we propose to characterize early cells of the osteoblast lineage in vivo. These cells are likely PTH targets (direct and indirect), but our ability to identify these cells and study how PTH changes them in vivo is limited. We will mark such early cells in the osteoblast lineage with a collagen 11-creERt transgene that will activate expression of a red fluorescent marker (tandem dimer tomato). We will determine the fates of such cells (how they differentiate into osteoblasts and adipocytes, how they proliferate and die, whether they participate in fracture repair). We will define their gene expression and will study how PTH changes their fates and activities in ways that may clarify the anabolic action of PTH and its limitations. We will also study bone lining cells to identify how PTH activates these cells to become active osteoblasts.
In Aim 2, we will study the roles of class IIa histone deacetylases (HDACs) in mediating PTH's action to suppress expression of sclerostin, a powerful inhibitor of wnt signaling secreted by osteocytes. We have shown that these HDACs mediate PTHrP's action in chondrocytes and hypothesize that, as in chondrocytes, HDACs respond to PTH by moving to the nucleus and suppressing transcription by Mef2 transcription factors. We will test this hypothesis using an osteocyte cell line from Dr. Divieti Pajevic and using knockout mice. We view sclerostin regulation as a model for many actions of PTH on all cells of the osteoblast lineage. Thus, by defining early cells of the lineage and a novel mediator of PTH signaling, we hope to clarify the mechanisms that can lead to more effective therapies.
Parathyroid hormone (PTH) is a powerful but limited therapy for osteoporosis. Our goal is to define early cells of the lineage of bone-forming cells that mediate actions of PTH and to define a signaling pathway key to the actions of PTH. With this work we hope to provide tools needed to develop more effective osteoporosis therapies.
|Bi, Ruiye; Fan, Yi; Lauter, Kelly et al. (2016) Diphtheria Toxin- and GFP-Based Mouse Models of Acquired Hypoparathyroidism and Treatment With a Long-Acting Parathyroid Hormone Analog. J Bone Miner Res 31:975-84|
|Stevenson, Hilary P; Lin, Guowu; Barnes, Christopher O et al. (2016) Transmission electron microscopy for the evaluation and optimization of crystal growth. Acta Crystallogr D Struct Biol 72:603-15|
|Ono, Noriaki; Kronenberg, Henry M (2016) Bone repair and stem cells. Curr Opin Genet Dev 40:103-107|
|Kim, Sang Wan; Lu, Yanhui; Williams, Elizabeth A et al. (2016) Sclerostin Antibody Administration Converts Bone Lining Cells into Active Osteoblasts. J Bone Miner Res :|
|Wein, Marc N; Liang, Yanke; Goransson, Olga et al. (2016) SIKs control osteocyte responses to parathyroid hormone. Nat Commun 7:13176|
|Eda, Homare; Santo, Loredana; Wein, Marc N et al. (2016) Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease. J Bone Miner Res 31:1225-34|
|Sinha, Partha; Aarnisalo, Piia; Chubb, Rhiannon et al. (2016) Loss of GsÎ± in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy. J Biol Chem 291:1631-42|
|Tenhola, Sirpa; Voutilainen, Raimo; Reyes, Monica et al. (2016) Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation. Eur J Endocrinol 175:211-8|
|Cheloha, Ross W; Watanabe, Tomoyuki; Dean, Thomas et al. (2016) Backbone Modification of a Parathyroid Hormone Receptor-1 Antagonist/Inverse Agonist. ACS Chem Biol 11:2752-2762|
|Hattersley, Gary; Dean, Thomas; Corbin, Braden A et al. (2016) Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. Endocrinology 157:141-9|
Showing the most recent 10 out of 195 publications