Regulation of Bone Remodeling by Parathyroid Hormone

Wein, Marc N.; Kronenberg, Henry M.

doi:10.1101/cshperspect.a031237

Cited by 171 publications

(135 citation statements)

References 174 publications

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“…Parathyroid hormone (PTH) is a calciotrophic hormone produced by the parathyroid glands. PTH is a critical regulator of skeletal development and postnatal skeletal maturation due to its capacity to stimulate both bone formation and bone resorption (1). Accordingly, lack of PTH leads to decreased trabecular bone in fetal and neonatal mice (2).…”

Section: Introductionmentioning

confidence: 99%

Parathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiota

Pal

et al. 2020

Journal of Clinical Investigation

113

114

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Section: Introductionmentioning

confidence: 99%

Parathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiota

Pal

et al. 2020

Journal of Clinical Investigation

113

114

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“…P arathyroid hormone (PTH) is a key calciotrophic hormone and a critical regulator of postnatal skeletal development 1 . Primary hyperparathyroidism, a condition characterized by chronic continuous overproduction of PTH by the parathyroid glands 2 , is modeled in animals by continuous PTH (cPTH) infusion 3 .…”

mentioning

confidence: 99%

PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells

Tyagi

et al. 2020

Nat Commun

113

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Bone loss is a frequent but not universal complication of hyperparathyroidism. Using antibiotic-treated or germ-free mice, we show that parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched by the Th17 cell-inducing taxa segmented filamentous bacteria (SFB). SFB + microbiota enabled PTH to expand intestinal TNF + T and Th17 cells and increase their S1P-receptor-1 mediated egress from the intestine and recruitment to the bone marrow (BM) that causes bone loss. CXCR3-mediated TNF + T cell homing to the BM upregulated the Th17 chemoattractant CCL20, which recruited Th17 cells to the BM. This study reveals mechanisms for microbiota-mediated gut-bone crosstalk in mice models of hyperparathyroidism that may help predict its clinical course. Targeting the gut microbiota or T cell migration may represent therapeutic strategies for hyperparathyroidism.

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“…BPs in the bone matrix directly inhibit osteoclast function (F). Both of these actions decrease calcium efflux into the extracellular space [1,2,9,15,16]. Fig.…”

Section: Normal Renal Calcium Handlingmentioning

confidence: 94%

“…PTH is involved in all three aspects of calcium metabolism via its action at the PTH-1 receptor: bone turnover, intestinal calcium absorption, and renal reabsorption of calcium. The action of PTH in bone involves its binding to receptors on osteoblasts, which leads to increased secretion of receptor activator of nuclear factor kappa-B ligand (RANKL), which in turn binds to RANK on osteoclasts, increasing their number and function [9]. This resorption of bone leads to calcium efflux (Fig.…”

Section: Pth and Calcium Homeostasismentioning

confidence: 99%

Cinacalcet for the Treatment of Humoral Hypercalcemia of Malignancy: An Introductory Case Report with a Pathophysiologic and Therapeutic Review

Sheehan

Tanimu

et al. 2020

Case Rep Oncol

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Hypercalcemia is an ominous development in the course of malignancy associated with a mean survival of only several months. A majority of cases of hypercalcemia are related to humoral hypercalcemia of malignancy (HHM), where hypercalcemia is caused by increased levels of circulating parathyroid hormone-related protein (PTHrP). Mainstay treatments in the management of HHM are intravenous fluids, intravenous bisphosphonates, and subcutaneous denosumab, although hypercalcemia oftentimes recurs despite these efforts. We present a case of advanced non-small cell lung cancer with PTHrP-mediated hypercalcemia that proved resistant to standard therapy. A trial of oral cinacalcet was initiated and improved calcium levels for 2 months despite a progressive rise in PTHrP and prior to subsequent disease progression. Based on the current body of literature, we propose that this calcium-lowering effect of cinacalcet occurs due to a potential effect on renal calcium excretion.Abnormal Renal Calcium Handling Related to PTHrP HHM is the most common etiology of malignancy-related calcium dysregulation and accounts for ∼80% of HCM cases [1,2]. Most often, it occurs in solid tumors of the lung, head and neck, esophagus, skin, cervix, breast, kidneys, prostate, and bladder [1, 2]. These patients do not have bone metastases, and hypercalcemia occurs via PTHrP actions in both the bones and kidneys [1,2]. PTHrP has some homology with PTH, especially at the amino-terminus, and binds to the PTH-1 receptor, resulting in increased skeletal efflux of calcium and increased renal reabsorption of calcium by the mechanisms described earlier for PTH ( Fig. 1A, 2, 3A).The relative contribution of each of these processes to hypercalcemia is unknown, but it is estimated that up to 1,000 mg of calcium per day may be mobilized from the skeleton in HHM [2]. Additionally, there is an underappreciated renal contribution to HHM, as evidenced by studies in both animals and humans. In rats with HHM refractory to bone resorption inhibitors, anti-PTHrP antibodies resulted in a marked decrease in blood calcium coinciding with a 2-to 3-fold increase in fractional excretion of calcium [13]. Furthermore, in normal human subjects infused with PTHrP, the fractional excretion of calcium (control group: ∼2%) increased by ∼50% less (∼2.5-3.7%) than the increase induced by a similar rise in serum

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Regulation of Bone Remodeling by Parathyroid Hormone

Abstract: See text for details and references. In addition, PTH used several indirect mechanisms to enhance bone formation and promote skeletal remodeling, as summarized in the text. OPG, Osteoprotegerin; IL, interleukin.

Cited by 171 publications

References 174 publications

Parathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiota

Parathyroid hormone–dependent bone formation requires butyrate production by intestinal microbiota

PTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells

Cinacalcet for the Treatment of Humoral Hypercalcemia of Malignancy: An Introductory Case Report with a Pathophysiologic and Therapeutic Review

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