Parathyroid hormone-related peptide and the hair cycle - is it the agonists or the antagonists that cause hair growth?

While the effects of PTHrP have been studied for almost 20 years, most of these studies have focused on effects on the termination of the anagen phase, giving an incomplete picture of the overall effect of PTHrP on the hair cycle. PTHrP was determined in several experimental models to promote transition of hair follicles from anagen to catagen phase, which by itself would suggest that PTHrP blockade might prolong the anagen phase and promote hair growth. However, clinical trials with topically applied PTHrP antagonists have been disappointing, leading to a reconsideration of this model. Additional studies performed in mouse models where hair follicles are damaged (alopecia areata, chemotherapy-induced alopecia) suggest that PTHrP has effects early in the hair cycle as well, promoting hair follicles' entry into anagen phase and initiates the hair cycle. While the mechanism of this has yet to be elucidated, it may involve activation of the Wnt pathway. Thus, the overall effect of PTHrP is to stimulate and accelerate the hair cycle, and in the more clinically relevant models of hair loss where hair follicles have been damaged or become quiescent, it is the agonists, not the antagonists, which would be expected to promote hair growth.

The IRE1α-XBP1 pathway positively regulates parathyroid hormone (PTH)/PTH-related peptide receptor expression and is involved in pth-induced osteoclastogenesis.

To address the "endoplasmic reticulum stress" triggered by the burden of protein synthesis, the unfolded protein response is induced during osteoblast differentiation. In this study, we show that the transcription of parathyroid hormone (PTH)/PTH-related peptide receptor (PTH1R) is regulated by one of the endoplasmic reticulum-stress mediators, the IRE1α-XBP1 pathway, in osteoblasts. We found that the increase in Pth1r transcription upon BMP2 treatment is significantly suppressed in mouse embryonic fibroblasts lacking IRE1α. As expected, gene silencing of Ire1α and Xbp1 resulted in a decrease in Pth1r transcripts in BMP2-treated embryonic fibroblasts. We identified two potential binding sites for XBP1 in the promoter region of Pth1r and found that XBP1 promotes the transcription of Pth1r by directly binding to those sites. Moreover, we confirmed that the gene silencing of Xbp1 suppresses PTH-induced Rankl expression in primary osteoblasts and thereby abolishes osteoclast formation in an in vitro model of osteoclastogenesis. Thus, the present study reveals potential involvement of the IRE1α-XBP1 pathway in PTH-induced osteoclastogenesis through the regulation of PTH1R expression.

Prevention and treatment of bronchopulmonary dysplasia: contemporary status and future outlook.

Despite tremendous advances in neonatology, bronchopulmonary dysplasia (BPD) remains a major cause of morbidity and mortality among premature infants. Any intervention that would reduce the risk of BPD or improve its outcome is likely to have substantial clinical and financial benefits. However, there is a clear lack of an effective agent for the treatment and/or prevention of BPD. This is due to an incomplete understanding of the molecular mechanisms involved in its pathogenesis. Taking a basic biological approach, our laboratory has discovered that disruption of normal alveolar homeostatic signaling is centrally involved in this process. Using a number of in vitro and in vivo models, our laboratory has demonstrated that stabilization of the normal alveolar homeostatic signaling pathway(s) can prevent and/or rescue the molecular injuries caused by the insults that lead to BPD. Here, we review the existing approaches to prevent and treat BPD and then, based on our insights into the pathogenesis of BPD, we propose novel and innovative therapeutic options that impact the disease on a cell/molecular level, unlike most of the current treatments available for BPD.

Exploiting the PTHrP signaling pathway to treat chronic lung disease.

Despite tremendous advances in intensive care in general and respiratory care in particular, chronic lung disease (CLD) still remains a major cause of morbidity and mortality both in the premature infant and adult. This is primarily due to a lack of understanding of the molecular mechanisms involved in both normal and abnormal lung development. Based on the cellular/molecular mechanisms involved in physiologic lung development, we have taken a basic biologic approach to elucidate the pathophysiology of CLD. Stretch regulated parathyroid hormone-related protein (PTHrP) signaling between the alveolar type II (ATII) cell and the mesoderm coordinately upregulates the key genes for the homeostatic fibroblast phenotype, which in turn stimulates surfactant synthesis by ATII cells. Under the influence of conditions that predispose to CLD, normal PTHrP signaling is disrupted and interstitial fibroblasts transdifferentiate to myofibroblasts, the hallmark cell of CLD. We have exploited the understanding of these molecular processes to demonstrate the proof-of-principle that by stabilizing the alveolar PTHrP signaling pathway using exogenously administered agonists of peroxisome proliferator-activated receptor-gamma a key target of PTHrP signaling, we can prevent and/or rescue the molecular injuries caused by insults that lead to CLD. Based upon extensive work from our laboratory, we suggest a novel and innovative molecular approach to prevent and/or treat fibrotic conditions in general and CLD in particular. However, to avoid any subsequent unexpected adverse consequences, it is important to emphasize that before translating the suggested approach into human trials, further testing and refinement in animal models is needed.

Prevention of bronchopulmonary dysplasia: finally, something that works.

Due to a lack of understanding of the molecular mechanisms involved in its pathogenesis, bronchopulmonary dysplasia (BPD) still remains a major cause of morbidity and mortality in the premature infant and there is no effective preventive and/or therapeutic intervention. We have taken a basic biologic approach to elucidate the pathophysiology of BPD and have discovered that disruption of the alveolar Parathyroid Hormone-related Protein (PTHrP) signaling is centrally involved in this process. Further, stabilization of this signaling pathway by using exogenous PTHrP agonists can prevent and/or rescue the molecular injuries caused by insults that lead to BPD. Based upon years of work in this field, here I provide a novel and innovative molecular approach, i.e, exogenous treatment with PTHrP pathway agonists to prevent and/or treat BPD. However, to avoid any later surprises, it is important to emphasize that before translating it into human trials, this approach needs further testing and refinement in animal models.

Cardiac-specific effects of parathyroid hormone-related peptide: modification by aging and hypertension.

OBJECTIVE: Parathyroid hormone-related peptide (PTHrP) improves heart function of post-ischemic and stunned myocardium and is released from the heart under ischemic conditions. Hypertrophic hearts from spontaneously hypertensive rats (SHR) develop a reduced ischemic tolerance, show reduced expression of PTHrP and develop paradoxical effects in regard to PTHrP. We hypothesized that PTHrP is causally involved in reduced ischemic tolerance of hypertrophied hearts. This hypothesis was tested by addition of a cardiac-specific PTHrP agonist or antagonist during ischemia and investigation of the functional recovery during the early phase of reperfusion. METHODS: Hearts from male normotensive adult (6 months) or old (12 months) Wistar and SHR rats were perfused at a constant flow for 20 min and then exposed for 30 or 15 min to global zero-flow ischemia followed by 30 min reperfusion. PTHrP agonist (PTHrP1-36) or antagonist (5Ile,23Trp,36Tyr-PTHrP1-36) (each 100 nmol/l) were added briefly before the onset of ischemia to ensure that they were present at the beginning of reperfusion. Heart function was determined by insertion of a balloon catheter into the left ventricle. Left ventricular developed pressure (LVDP), dP/dtmax, dP/dtmin, left ventricular end-diastolic pressure (LVeDP), heart rate (HR) and coronary resistance (CR) were recorded. RESULTS: Reduced post-ischemic recovery in old SHR was confirmed. Hearts from all four groups responded normally to exogenous PTHrP with a positive chronotropic effect under non-ischemic conditions. In hearts from adult normotensive rats, a beneficial effect of released endogenous PTHrP was confirmed. However, addition of the cardiac-specific PTHrP antagonist during ischemia significantly improved post-ischemic recovery in hearts from old normotensive rats and SHR. This beneficial effect of the antagonist was accompanied by a significant reduction in post-ischemic LVeDP and was more pronounced in adult SHR. This effect was also observed when the hearts were paced (4 Hz). Upon short-term ischemia (15 min), in the absence of ischemia-induced rigor contraction, the antagonist improved LVDP recovery in hearts from old normotensive rats. CONCLUSION: In summary, a protective effect of released endogenous PTHrP was confirmed for hearts from adult normotensive rats. This effect is converted into an opposite effect in hearts from SHR and old normotensive rats. Therefore, released endogenous PTHrP can contribute to reduced ischemic tolerance in hypertrophied hearts and during aging.