T Lymphocytes Amplify the Anabolic Activity of Parathyroid Hormone through Wnt10b Signaling

Terauchi, Masakazu; Li, Jau‐Yi; Bedi, Brahmchetna; Baek, Kwang‐Hyun; Tawfeek, Hesham A.; Galley, Sarah A.; Gilbert, Linda; Nanes, Mark S.; Zayzafoon, Majd; Guldberg, Robert E.; Lamar, David L.; Singer, Meredith A.; Lane, Timothy F.; Kronenberg, Henry M.; Weitzmann, M. Neale; Pacifici, Roberto

doi:10.1016/j.cmet.2009.07.010

Cited by 183 publications

(301 citation statements)

References 57 publications

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“…Unlike other osteoporosis agents, PTH is an osteoanabolic that actually promotes bone formation when administered at low doses intermittently. Although the cellular mechanisms by which this occurs are still unclear, it is likely that the Wnt signaling pathway (via suppression of sclerostin), (4,5) Runx2, receptor activator of NF-kB ligand (RANKL), osteoprotegerin, and insulinlike growth factor are all involved. (6)(7)(8) The stimulation of bone formation that results may first occur on quiescent bone surfaces, akin to bone modeling that occurs in the growing skeleton.…”

Section: Pth Mechanisms Of Actionmentioning

confidence: 99%

Safety of osteoanabolic therapy: A decade of experience

Capriani

Irani

Bilezikian

2012

Journal of Bone and Mineral Research

132

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IntroductionO steoporosis is a prevalent disease that affects more than 10 million Americans. The lifetime risk of an osteoporosisrelated fracture is 50% for Caucasian women and 25% for men. Hip fractures carry a 10% to 20% increase in mortality rate within the first year after fracture. (1) The burden of the hip and other fractures can result in chronic pain, disability and other indices of reduced quality of life.Amidst these sobering statistics is the welcome advent over the past two decades of effective pharmacological therapies that reduce fracture risk. The therapies approved for the management of osteoporosis include bisphosphonates, raloxifene (a selective estrogen-receptor modulator), calcitonin, denosumab, strontium ranelate, and parathyroid hormone and PTH(1-84)]. The fulllength PTH molecule and its foreshortened amino-terminal fragment (teriparatide) are currently the only osteoanabolic agents approved for use. PTH(1-84) is not available in the United States. In November, 2002, teriparatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis and, later, in men. The approval came with restrictions in duration of therapy (18-24 months) and was limited to individuals with advanced osteoporosis at high risk for fracture. Reasons for these limitations relate, at least in part, to the unexpected occurrence of osteosarcoma and other bone neoplasms in Fischer 344 rat toxicity studies. In fact, the pivotal phase 3 trial of teriparatide was suspended when these rat toxicity data became available. The effects on rats was doseand duration-dependent, with rats being treated for approximately 80% of their lifetime and at doses three to 58 times the currently approved human dose. (2) Similar toxicity was seen for PTH(1-84) (3) Given the clear-cut efficacy data when the results of the abbreviated clinical trial results for teriparatide were analyzed, the FDA and equivalent other agencies in Europe and elsewhere granted approval of teriparatide with the stipulations that it should be used for no longer than 2 years. In the United States, the drug carries a ''black box warning'' and contraindicates its use in patients with existing risk factors for osteosarcoma, including Paget's disease of bone, prior skeletal radiation, and children with open epiphyses.Teriparatide has now been used in the United States for 10 years. With a decade of experience, it is timely to review the efficacy and safety profile of this medication. PTH(1-84) will also be reviewed. This perspective will be limited to PTH formulations that are available for the treatment of osteoporosis; we will not be discussing other anabolic agents that are currently being studied but are not yet approved, such as the sclerostin antibody (http://clinicaltrials.gov/ct2/results?term ¼ sclerostin þ anti-þ antibody). PTH mechanisms of actionTeriparatide is an amino-terminal fragment of PTH that is biologically identical to the amino-terminal fragment of human PTH. This fragment contains all the classical bio...

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Section: Pth Mechanisms Of Actionmentioning

confidence: 99%

Safety of osteoanabolic therapy: A decade of experience

Capriani

Irani

Bilezikian

2012

Journal of Bone and Mineral Research

132

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“…With the exception of specific PPRexpressing T-cell subpopulations, 6,7 PTH actions on hematopoiesis are thought to be mediated via paracrine or juxtacrine signaling from PPR-activated stromal osteoblastic cells. 1,2,8 PPR signaling in stromal osteoblastic cells alters the expression of osteoclastic cytokines, most notably receptor activator of nuclear factor-B ligand (RANKL) and osteoprotegerin (OPG), which regulate the differentiation of hematopoietic cells to mature bone resorbing osteoclastic cells.…”

mentioning

confidence: 99%

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Novince¹,

Koh²,

Michalski³

et al. 2011

The American Journal of Pathology

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Proteoglycan 4 (PRG4), a critical protective factor in articular joints, is implicated in hematopoietic progenitor cell expansion and megakaryopoiesis. PRG4 loss-of-function mutations result in camptodactyly-arthropathy-coxa varapericarditis (CACP) syndrome, which is characterized primarily by precocious joint failure. PRG4 was identified as a novel parathyroid hormone (PTH) responsiveness gene in osteoblastic cells in bone, and was investigated as a potential mediator of PTH actions on hematopoiesis. Sixteen-week-old Prg4 ؊/؊ mutant and Prg4 ؉/؉ wild-type mice were treated daily with intermittent PTH (residues 1-34) or vehicle for 6 weeks. At 22 weeks of age, Prg4 mutant mice had increased peripheral blood neutrophils and decreased marrow B220 ؉ (B-lymphocytic) cells, which were normalized by PTH. The PTH-induced increase in marrow Lin ؊ Sca-1 ؉ c-Kit ؉ (hematopoietic progenitor) cells was blunted in mutant mice. Basal and PTHstimulated stromal cell-derived factor-1 (SDF-1) was decreased in mutant mice, suggesting SDF-1 as a candidate regulator of proteoglycan 4 actions on hematopoiesis in vivo. PTH stimulation of IL-6 mRNA was greater in mutant than in wild-type calvaria and bone marrow, suggesting a compensatory mechanism in the PTH-induced increase in marrow hematopoietic progenitor cells. In summary, proteoglycan 4 is a novel PTH-responsive factor regulating immune cells and PTH actions on marrow hematopoietic progenitor cells.

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“…No significant increase in BV/TV or trabecular bone mineral density (BMD) with even the high dose of 100 mg/kg per day of PTH after 9 weeks of treatment was detected in wild-type (C57Bl/6) mice of this age. This is an issue of some concern, particularly because others have shown dramatic effects of PTH on both these parameters in wild-type mice of C57Bl/6, (13,14) DBA/1, (15) mixed strain, (16) or unspecified strain (17,18) of this age or younger. It should be noted that in these other studies it is only the treatment regimen of Terauchi and colleagues (14) that is directly comparable.…”

mentioning

confidence: 99%

“…This is an issue of some concern, particularly because others have shown dramatic effects of PTH on both these parameters in wild-type mice of C57Bl/6, (13,14) DBA/1, (15) mixed strain, (16) or unspecified strain (17,18) of this age or younger. It should be noted that in these other studies it is only the treatment regimen of Terauchi and colleagues (14) that is directly comparable. The difference in response to PTH between the work of Kramer and colleagues and Terauchi and colleagues is particularly perplexing.…”

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confidence: 99%

Building bone with a SOST-PTH partnership

Sims

2010

Journal of Bone and Mineral Research

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T he discovery of the SOST gene, whose protein product, sclerostin, is an osteocyte-derived inhibitor of Wnt signalling and bone formation, (1,2) has provided a major advance in bone biology. It gives us new insights into the communicating networks among bone cells and, importantly, to new ways of restoring bone once it has been lost. In the current issue of JBMR, Kramer and colleagues complement their earlier demonstration that parathyroid hormone (PTH) inhibits sclerostin expression (3) to show that the anabolic effect of PTH is blunted both in mice overexpressing sclerostin and in SOST null mice. (4) PTH administered by daily injection is the only currently available anabolic therapy for bone. (5,6) While a number of contributing pathways, including direct prodifferentiation (7) and antiapoptotic (8) actions on osteoblasts, as well as couplingrelated activity through the osteoclast, (9) have been proposed, the full mechanism of action of anabolic PTH remains obscure. Another contributory mechanism was introduced by the discovery of sclerostin and its regulation by both PTH and PTH-related protein (PTHrP) via a distal enhancer of the SOST gene. (3,10) The experiments reported by Kramer and colleagues (4) provide further evidence that sclerostin regulation may play a part in PTH anabolic action. Mice overexpressing sclerostin have less bone as a result of decreased bone-formation rate, as described previously. (11) When these mice were treated with a high dose of PTH, sufficient to increase trabecular bone volume (BV/TV) in wild-type mice, no increase in trabecular bone volume was detected despite a robust reduction in sclerostin expression. It is worth noting that even though sclerostin mRNA levels are reduced by PTH in the transgenic model, total sclerostin expression after PTH treatment is still greater than in wild-type mice. This high level of sclerostin expression, the basal phenotype of a mild reduction in bone remodeling, or both impair the effect of PTH on BV/TV. Surprisingly, even though BV/ TV was not increased, all histomorphometric markers of bone formation, as well as the osteoclast surface, were substantially elevated by PTH treatment in the sclerostin transgenic mice to approximately the same extent as that observed in wild-type mice. Thus a question in the sclerostin transgenic model remains as to how PTH can increase bone turnover without altering BV/ TV. Is osteoclast function enhanced? No evidence was obtained for that. An alternative explanation could be that the sclerostin overexpressing mice lay down bone of reduced quality that is easier for osteoclasts to resorb. The quality of bone in the sclerostin overexpressing mouse is not yet known. Resolving this paradox may provide useful information about the interaction between osteoclasts and osteoblasts in the presence of high levels of sclerostin and, presumably, low levels of b-cateninactivated gene transcription.In SOST null mice, as expected from the skeletal abnormalities observed in van Buchem disease and sclerosteosis, (12) trabecular...

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T Lymphocytes Amplify the Anabolic Activity of Parathyroid Hormone through Wnt10b Signaling

Cited by 183 publications

References 57 publications

Safety of osteoanabolic therapy: A decade of experience

Safety of osteoanabolic therapy: A decade of experience

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Building bone with a SOST-PTH partnership

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