Increased PTHrP and Decreased Estrogens Alter Bone Turnover but Do Not Reproduce the Full Effects of Lactation on the Skeleton

Ardeshirpour, Laleh; Brian, Susan; Dann, Pamela; VanHouten, Joshua; Wysolmerski, John J.

doi:10.1210/jcem.95.12.9987

Cited by 9 publications

(11 citation statements)

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“…An estimation of osteocyte‐dependent acidification has been recently made by the group of Sano and colleagues, suggesting that osteocytic osteolysis occurs around pH = 5.9. We know that a large amount of calcium mobilization during lactation is accomplished by osteoclasts, yet osteocytic osteolysis seems to be inducible early during lactation ensuring initial calcium supply . Moreover, in comparison to fibroblasts and even osteoblasts, osteocytes demonstrated increased survival rates at low pH.…”

Section: Discussionmentioning

confidence: 99%

Osteocytes Acidify Their Microenvironment in Response to PTHrP In Vitro and in Lactating Mice In Vivo

Jähn

Kelkar

Zhao

et al. 2017

Journal of Bone and Mineral Research

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Osteocytes appear to mobilize calcium within minutes in response to PTH injections and we have previously shown that osteocytes remove their perilacunar matrix during lactation through activation of the PTH type 1 receptor. Mechanisms utilized by osteocytes to mobilize calcium are unknown but we hypothesized that the molecular components may be similar to those used by osteoclasts. Here we show, using IDG-SW3 cells that ATP6V0D2, an essential component of vacuolar ATPase in osteoclasts, and other genes associated with osteoclastic bone resorption increase with osteoblast to osteocyte differentiation. Furthermore, PTHrP increases ATP6V0D2 expression and induces proton generation by primary osteocytes, which is blocked by bafilomycin, a vacuolar ATPase inhibitor. These in vitro proton measurements raised the question of osteocyte viability in an acidic environment. Interestingly, osteocytes, showed enhanced viability at pH as low as 5 compared to osteoblasts and fibroblasts in vitro. To study in vivo acidification by osteocytes, virgin and lactating CD1 mice on a low calcium diet were injected with the pH indicator dye, acridine orange, and their osteocyte lacuno-canalicular system imaged by confocal microscopy. Lower pH was observed in lactating compared to virgin animals. In addition, a novel transgenic mouse line with a GFPtpz-tagged collagen α2(I) chain was used. Instead of the expected reduction in GFP-fluorescence only in the perilacunar matrix, reduced fluorescence was observed in the entire bone matrix of lactating mice. Based on our experiments showing quenching of GFP in vitro, we propose that the observed reduction in GFP fluorescence in lactating mice is due to quenching of GFP by the acidic pH generated by osteocytes. Together these findings provide novel mechanistic insight into how osteocytes remove calcium from their perilacunar/pericanalicular matrices through active acidification of their microenvironment and show that osteocytes, like osteoclasts, are resistant to the negative effects of acid on viability.

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Section: Discussionmentioning

confidence: 99%

Osteocytes Acidify Their Microenvironment in Response to PTHrP In Vitro and in Lactating Mice In Vivo

Jähn

Kelkar

Zhao

et al. 2017

Journal of Bone and Mineral Research

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“…Both PTHrP and low estradiol are required for normal lactational bone loss to occur, because treatment with supraphysiological doses of estradiol, or ablation of the PTHrP gene from mammary tissue, blunted but did not obliterate the bone loss. Other hormones may also regulate bone metabolism during lactation …”

Section: Introductionmentioning

confidence: 99%

Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone

Kirby

Martin

et al. 2013

Journal of Bone and Mineral Research

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Pregnancy invokes a doubling of intestinal calcium absorption whereas lactation programs skeletal resorption to provide calcium to milk. Postweaning bone formation restores the skeleton's bone mineral content (BMC), but the factors that regulate this are not established. We used Pth-null mice to test whether parathyroid hormone (PTH) is required for postweaning skeletal recovery. On a normal 1% calcium diet, wild-type (WT) and Pth-null mice each gained BMC during pregnancy, declined 15% to 18% below baseline during lactation, and restored the skeleton above baseline BMC within 14 days postweaning. A 2% calcium diet reduced the lactational decline in BMC without altering the gains achieved during pregnancy and postweaning. The hypocalcemia and hyperphosphatemia of Pth-null mice normalized during lactation and serum calcium remained normal during postweaning. Osteocalcin and propeptide of type 1 collagen (P1NP) each rose significantly after lactation to similar values in WT and Pth-null. Serum calcitriol increased fivefold during pregnancy in both genotypes whereas vitamin D binding protein levels were unchanged. Absence of PTH blocked a normal rise in fibroblast growth factor-23 (FGF23) during pregnancy despite high calcitriol. A 30-fold higher expression of Cyp27b1 in maternal kidneys versus placenta suggests that the pregnancy-related increase in calcitriol comes from the kidneys. Conversely, substantial placental expression of Cyp24a1 may contribute significantly to the metabolism of calcitriol. In conclusion, PTH is not required to upregulate renal expression of Cyp27b1 during pregnancy or to stimulate recovery from loss of BMC caused by lactation. A calcium-rich diet in rodents suppresses skeletal losses during lactation, unlike clinical trials that showed no effect of supplemental calcium on lactational decline in BMC.

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“…Oxytocin stimulates milk ejection, but its local expression and receptor within bone may mean that it directly modulates bone turnover [23,24]. PTHrP may be more important because deletion of its gene from mammary tissue reduced lactational bone loss in mice [27], in which isolated estradiol deficiency from ovariectomy leads to relatively slow loss of bone [3,28]. Increased circulating PTHrP and low estradiol synergize to increase bone resorption [3].…”

Section: Skeletal Physiology During Pregnancymentioning

confidence: 99%

Osteoporosis presenting in pregnancy, puerperium, and lactation

Kovacs

2014

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Increased PTHrP and Decreased Estrogens Alter Bone Turnover but Do Not Reproduce the Full Effects of Lactation on the Skeleton

Cited by 9 publications

References 0 publications

Osteocytes Acidify Their Microenvironment in Response to PTHrP In Vitro and in Lactating Mice In Vivo

Osteocytes Acidify Their Microenvironment in Response to PTHrP In Vitro and in Lactating Mice In Vivo

Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone

Osteoporosis presenting in pregnancy, puerperium, and lactation

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