Daily injections of parathyroid hormone (PTH) amino-terminal peptide 1-34, a regiment known as intermittent PTH (iPTH) treatment, stimulate bone formation and reduce the incidence of fracture in postmenopausal women and in elderly men. The increase in bone formation caused by intermittent PTH is mainly due to an increase in osteoblast (OB) number. The prevailing explanations for this are increased osteoblastogenesis, attenuation of pre-OB and OB apopotosis, activation of quiescent lining cells, and signaling in osteocytes. PTH binds to the PTH/PTH-related protein (PTHrP) receptor (PPR or PTH-1R), which is expressed on osteoblasts (OBs), osteocytes and bone marrow (BM) stromal cells (SCs). T Lymphocytes also express PPR, respond to PTH, and stimulate OB differentiation. We have found that the capacity of iPTH to augment bone formation, trabecular bone volume and bone strength is markedly reduced in T cell deficient mice, and restored by adoptive transfer of T cells into T cell deficient mice. These findings suggest that PTH signaling in cells of the osteoblastic lineage is necessary but not sufficient for iPTH to induce maximal bone growth, which indicates that T cells play a previously unrecognized role in the anabolic actions of iPTH. However, the mechanism by which T cells contribute to PTH induced bone anabolism remains to be characterized. Equally enigmatic is whether iPTH targets T cells directly or indirectly. Our preliminary studies suggest that iPTH increases the T cell production of Wnt10b, a Wnt ligand that stimulates osteoblastogenesis by activating Wnt signaling in SCs and OBs. Our initial findings also show that the capacity of iPTH to induce T cell production of Wnt10b is abolished by silencing of the PTH receptor PPR in T cells. Based on these data we hypothesize that iPTH treatment directly stimulates T cells to produce Wnt10b, which leads to increased osteoblastogenesis through activation of the Wnt pathway in SCs and their osteoblastic progeny. Others have demonstrated that PTH stimulates bone anabolism by decreasing the production of Sclerostin, a Wnt inhibitor produced by osteocytes. Based on the published evidence from us and others, we propose the hypothesis that iPTH exerts its anabolic activity by activating Wnt signaling in OBs trough a double effect. The first is an increase in the production of the osteogenic Wnt ligand Wnt10b by BM CD8+ T cells. The second is an increase in the sensitivity of the Wnt receptor complex to Wnt ligands induced by inhibition of the osteocytic production of Sclerostin.
The specific Aims to investigate the hypothesis are:
Specific Aim 1) To determine the role of CD8+ T cell produced Wnt10b in the mechanism by which iPTH induces bone anabolism.
Specific Aim 2) To determine whether direct PPR signaling in T cells is required for T cells to potentiate the anabolic activity of iPTH.
Specific Aim 3) To determine the effects on bone anabolism of iPTH treatment in Sost-/- mice and in Sost -/- mice lacking T cell production of Wnt10b. This proposal may reveal a novel relevant role of T cells in the anabolic activity of PTH in bone.
We propose a study to elucidate the role of T cells in the mechanisms of the anabolic effect of parathyroid hormone (PTH) in bone. An enhanced insight of how T cells contribute to PTH induced bone anabolism will provide new perspectives for the treatment of osteoporosis.
|Li, Jau-Yi; Chassaing, Benoit; Tyagi, Abdul Malik et al. (2016) Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest 126:2049-63|
|Alvarez, Jessica A; Ziegler, Thomas R; Millson, Erin C et al. (2016) Body composition and lung function in cystic fibrosis and their association with adiposity and normal-weight obesity. Nutrition 32:447-52|
|Grassi, Francesco; Tyagi, Abdul Malik; Calvert, John W et al. (2016) Hydrogen Sulfide Is a Novel Regulator of Bone Formation Implicated in the Bone Loss Induced by Estrogen Deficiency. J Bone Miner Res 31:949-63|
|Robinson, Jerid W; Li, Jau-Yi; Walker, Lindsey D et al. (2015) T cell-expressed CD40L potentiates the bone anabolic activity of intermittent PTH treatment. J Bone Miner Res 30:695-705|
|Li, Jau-Yi; D'Amelio, Patrizia; Robinson, Jerid et al. (2015) IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice. Cell Metab 22:799-810|
|Li, Jau-Yi; Walker, Lindsey D; Tyagi, Abdul Malik et al. (2014) The sclerostin-independent bone anabolic activity of intermittent PTH treatment is mediated by T-cell-produced Wnt10b. J Bone Miner Res 29:43-54|
|Li, Jau-Yi; Adams, Jonathan; Calvi, Laura M et al. (2013) Ovariectomy expands murine short-term hemopoietic stem cell function through T cell expressed CD40L and Wnt10B. Blood 122:2346-57|
|Bedi, Brahmchetna; Li, Jau-Yi; Tawfeek, Hesham et al. (2012) Silencing of parathyroid hormone (PTH) receptor 1 in T cells blunts the bone anabolic activity of PTH. Proc Natl Acad Sci U S A 109:E725-33|