Increase Stature with Parathyroid Hormone?

The Parathyroid and Thyroid oppose each other in function.  The parathyroid increases calcium concentration whereas the thyroid decreases calcium concentration.  If levels of Parathyroid Hormone are sufficiently elevated then you can begin to form calcium deposits.  These calcium deposits can form anywhere even on the top of your skull or bottom of your foot which would technically increase height.

Parathyroid Hormone also plays a role in increasing levels of 25-hydroxyvitamin D3 which plays a role in the growth plate.  High levels of Parathyroid Hormone increases osteoclast activity by increasing osteoblast RANKL expression which lowers bone mine mineral content.  The bone heads into the blood but the bone is now highly susceptible to fracture.  So you could obtain an effect like I hypothesized for Kojima's clinic where the decreased bone mineral content of bone allows one to easily stretch the bone.  Lithium consumption may encourage hyperparathyroid activity.  Lithium consumption encourages stem cell proliferation everywhere so it only makes sense that the parathyroid undergoes that same stem cell proliferation.

Hyper expression of parathyroid hormone also makes the bones more susceptible to fracture and fracture creates space in the bone which when healed will result in a longer bone. 

It's clear that Parathyroid Hormone has a lot of potential for possible applications in height increase but there first must be found a way to control the calcium deposits and manage the reduced bone mineral content.  Because after you stretch the bone, you want the bone to reach it's normal bone mineral content levels.

Parathyroid Hormone release may also play a role in loss of growth plate function.

Active role of chondrocyte apoptosis in endochondral ossification.

"From observations of key features of apoptosis, including activation of the caspase cascade, changes in mitochondrial function, and expression of apoptosis inhibitors, the commitment of chondrocytes to apoptosis, appears to occur very early in hypertrophic differentiation. It is proposed that these changes produce effects that go far beyond the process of cell death and exert a focal influence on the endochondral ossification processes occurring in the microenvironment of the growth cartilage vascular interface. Endochondral ossification processes mediated by chondrocyte apoptosis may include intracellular calcium accumulation and release[Which is regulated by Parathyroid Hormone]; matrix calcification; matrix resorption; maintenance of growth plate homeostasis; attraction of blood vessels and osteoblast precursors; and stimulation of bone formation."

"A homeostatic mechanism must exist to maintain the rate of cell proliferation, matrix production, and cell death in order to keep the growth plate at its standard size.A small, persistent imbalance between the rate of cell production and the rate of cell death would lead to loss or overgrowth of the growth plate. The growth factor loop involving PTHrP and Indian hedgehog (IHH), recently demonstrated, is a clearly important mechanism for control of endochondral ossification. IHH appears to diffuse from its site of
expression in chondrocytes committed to hypertrophic differentiation, to the perichondrium. In the perichondrium[immature periosteum which is attached to chondrocytes rather than bone] IHH causes the release of PTHrP, which then acts as a negative feedback to prevent or delay chondrocyte
hypertrophy. In a developing bone anlagen, the distance between the IHH producing chondrocyte and the responsive perichondrium is only a few cell diameters. As an animal develops and the distance between the perichondrium and chondrocytes increases, the role played by communication between perichondrium and hypertrophic chondrocytes would be expected to decrease and the role played by communication between apoptotic hypertrophic chondrocytes and more immature chondrocytes, a few cells above them in the growth plate, would be expected to increase."<-The lack of communication of the pericardium and chondrocytes may be a reason why growth eventually stops however growth may be able to go on by means of communication between the chondrocytes themselves.  As the bone matures more and more of the periosteum becomes attached to bone rather than cartilage.  Maybe this aging of the bone can be reversed by means of a parathyroid stimulating substance like teriparatide.

"In the growth plate, one candidate for a source of regulatory signals is chondrocyte apoptosis and one of the signals may be TGF-b[TGF-b seems to be secreted by osteoblasts in response to fluid flow]. The presence of TGF-b in high concentration in terminal hypertrophic chondrocytes, its secretion and activation associated with apoptosis, together with the importance of TGF-b receptors in growth plate structure makes TGF-b and chondrocyte apoptosis appealing candidates as part of a mechanism for maintaining growth plate homeostasis. TGF-b, transported from apoptotic chondrocytes back through the growth plate to the region of cell division, would be expected to stimulate matrix production, delay hypertrophic differentiation, and thus maintain growth plate width by coupling resorption with growth."<-If TGF-Beta is a key regulating factor after PTH and IHH is no longer able to regulate.  Stimulating TGF-B release from osteoblasts would seem like a key signal to stimulate chondrogenesis.

A mathematical model of calcium and phosphorus metabolism in two forms of hyperparathyroidism.

"Parathyroid hormone (PTH) plays a critical role in calcium and phosphorus metabolism. Interestingly, in two forms of hyperparathyroidism (excessive amount of PTH in the serum), the metabolic disturbances in patients with chronic kidney disease (CKD) significantly differ from those with primary hyperparathyroidism (PHP).  We developed a mathematical model using clinical data (1586 CKD and 40 PHP patients). The model was composed of a set of ordinary differential equations, in which the regulatory mechanism of PTH together with other key factors such as 1,25-Dihydroxyvitamin D (1,25(OH)(2)D) and calcium was described in the tissues including bone, the kidney, the serum, and the parathyroid glands. In this model, an increase in PTH was induced by its autonomous production in PHP, while PTH in CKD was elevated by a decrease in feedback inhibition of 1,25(OH)(2)D in the serum, as well as an increase in stimulation by phosphorus in the serum[So Vitamin D decreases PTH and phosphorus increases PTH]. The model-based analysis revealed characteristic differences in the outcomes of hyperparathyroidism in CKD and PHP. The calcium exchange in bone, for instance, was predicted significantly higher in PHP than CKD. Calcimimetics [is] a recently developed synthetic drug that modulated efficacy of calcium-sensing receptors."

Parathyroid Hormone inhibits further chondrocyte differentiation by phosphorylating Sox9.

The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones

"In the growth plate of endochondral bones, parathyroid hormone (PTH)-related peptide (PTHrP) regulates the rate of chondrocyte maturation from prehypertrophic chondrocytes to hypertrophic chondrocytes. Using an antibody specific for Sox9 phosphorylated at serine 181 (S181), one of the two consensus protein kinase A phosphorylation sites of Sox9, we showed that the addition of PTHrP strongly increased the phosphorylation of SOX9 in COS7 cells transfected with both SOX9- and PTH/PTHrP receptor-expressing vectors. PTHrP also increased the SOX9-dependent activity of chondrocyte-specific enhancers in the gene for type II collagen (Col2a1) in transient transfection experiments. This increased enhancer activity did not occur with a Sox9 mutant harboring serine-to-alanine substitutions in its two consensus protein kinase A phosphorylation sites. Consistent with these results, PTHrP also increased Col2a1 mRNA levels in rat chondrosarcoma cells as well as 10T1/2 mesenchymal cells transfected with a PTH/PTHrP receptor expressing plasmid. No phosphorylation of Sox9 at S181 was detected in prehypertrophic chondrocytes of the growth plate or any chondrocytes of PTH/PTHrP receptor null mutants. In contrast in wild-type mouse embryos, previous immunohistochemistry experiments indicated that Sox9 phosphorylated at S181 was detected almost exclusively in chondrocytes of the prehypertrophic zone. Sox9, regardless of the phosphorylation state, was present in all chondrocytes of both genotypes except hypertrophic chondrocytes. Our results indicated that Sox9 is a target of PTHrP signaling in prehypertrophic chondrocytes in the growth plate. We hypothesize that Sox9 mediates at least some effects of PTHrP in the growth plate and that the PTHrP-dependent increased transcriptional activity of Sox9 helps maintain the chondrocyte phenotype of cells in the prehypertrophic zone and inhibits their maturation to hypertrophic chondrocytes."

"transgenic mice having expression of this mutant PTH/PTHrP receptor have demonstrated slower conversion of proliferating chondrocytes into hypertrophic chondrocytes"

"SOX9 contains two consensus phosphorylation sites for cAMP-dependent protein kinase A (PKA) and that PKA phosphorylation of SOX9 increases its DNA binding and transcriptional activities"

Parathyroid hormone enhances early and suppresses late stages of osteogenic and chondrogenic development in a BMP-dependent mesenchymal differentiation system (C3H10T1/2).

"The role of parathyroid hormone (PTH) upon osteo-/chondrogenic development was investigated in a bone morphogenetic protein (BMP)-dependent differentiation system involving the recombinant expression of BMPs in mesenchymal progenitor cells (C3H10T1/2). The constitutive expression of the PTH/PTH related protein receptor in this system led to a marked stimulation of chondrogenic and osteogenic development, while the permanent application of the ligand PTH(1-34) resulted in opposite responses by stimulating the early and suppressing the late stages of osteo-/chondrogenic development. These contrasting effects of PTH(1-34) on osteogenic and chondrocytic development seem, therefore, to depend on the cellular state of differentiation. The osteogenic and chondrocytic differentiation potential was substantiated histologically and by genetic analyses of marker genes like c-fos, alkaline phosphatase, osteocalcin, collagen alpha1(I), and collagen alpha1(II). The capacity to regulate osteogenic and chondrogenic development is located in the amino-terminal (1-34) region of the PTH molecule and seems to be mediated by the cyclic adenosine monophosphate signaling cascade. The application of other PTH domains like PTH(28-48) and PTH(53-84) did not exhibit significant responses. PTH acts as an essential factor in mesenchymal development controlling rates of differentiation into the osteogenic or chondrogenic lineage."

"The PTH/PTHrP receptor has been cloned and characterized as a G-coupled receptor containing seven transmembrane domains. PTHrP and PTH bind this receptor on the surface of osteoblastic, chondrocytic, and renal epithelial cells specifically through a conserved 34 amino acid amino-terminal region. Binding of either ligand leads to an increase in intracellular cyclic adenosine monophosphate (cAMP) synthesis, raises the intracellular level of calcium, and stimulates inositol 1,4,5-trisphosphate production."

"overexpression of the PTH/PTHrP receptor in BMP-expressing C3H10T½ cells dramatically enhance chondrogenic and osteogenic development"

C-fos expression was high with PTHR transgenic at days 0,2, and 15.  COL2A1 expression was high from days 0-15.

"Application of the ligand PTH(1–34) enhances chondrogenic development in C3H10T½BMP2 cells but suppresses chondrogenesis in C3H10T½BMP2-PTHR cells. The inhibitory effect of the ligand PTH(1–34) upon rates of chondrocytic differentiation of C3H10T½BMP2-PTHR cells suggests that high levels of activated PTH/PTHrP receptor suppress chondrogenic development, and that modest levels of activated PTH/PTHrP-receptor as present in C3H10T½BMP2-PTHR cells or in PTH(1–34)–treated C3H10T½BMP2 cells are stimulatory for ongoing chondrogenesis"

"Forskolin was capable of mimicking PTH(1–34) activities in C3H10T½BMP2-PTHR cells"

"a patient with a mutation resulting in a constitutively active PTH/PTHrP receptor [exhibited] a permanent ligand-independent cAMP synthesis. Besides abnormalities in the mineral homeostasis, this patient suffered from a rare form of short-limbed dwarfism (Jensen-type metaphyseal chondrodysplasia)."

Novel early target genes of parathyroid hormone-related peptide in chondrocytes.

"ATDC5 cells were cultured as micromasses to induce chondrocyte differentiation. On d 8 of culture, the cells had a prehypertrophic appearance. This time point was chosen for isolation of RNA at 0, 1, 2, and 4 h after a challenge with 10(-7) M PTHrP.  PTHrP is able to positively regulate the activity of Stat3-specific and negatively regulate the activity of Stat5-specific promoter-reporter constructs in ATDC5 and UMR106 cells. PTHrP and Janus kinase/Stat signaling [are connected]."

Genes upregulated by PTHrP in chondrocytes also upregulated by LSJL:

Sgk

Genes downregulated:

Uchl5

Eef1a1

PTHrP increased Stat5b{down in LSJL} expression in as low as 1 hour.

"the responsiveness of ATDC5 cells to PTHrP increased during differentiation. We decided to stimulate the micromasses on d 8 with PTHrP. At this time point, chondrocytes respond to PTHrP and have prehypertrophic characteristics, as demonstrated by the expression of collagen type IX. Late-proliferating and prehypertrophic cells are the main target cells of PTHrP in the growth plate. The higher levels of collagen X expression on d 14 of culture suggested that more cells had undergone chondrocyte hypertrophy at this time point."

Here's a study that suggests that parathyroid hormone may not affect longitudinal growth:

Cinacalcet does not affect longitudinal growth but increases body weight gain in experimental uraemia.

"Cinacalcet (CIN) efficiently suppresses parathyroid hormone (PTH) secretion by the activation of the calcium-sensing receptor (CaR). Epiphyseal chondrocytes also express the CaR and its activation promotes cell proliferation and differentiation in vitro.
We treated subtotally nephrectomized (SNX)[kidney removal] and sham-operated, ad lib[animals can eat freely] and pair-fed[food consumption is the same between all animals] Sprague-Dawley rats with CIN (15 mg/kg day) or solvent (S) for 14 days p.o. and assessed whole body and tibia length gain, growth plate morphology, osseous front advance (OFA) (calcein staining) and chondrocyte proliferation rate [5-bromo-2'-deoxyuridine (BrdU) staining].
Total body length gain did not differ after 7 and 14 days (SNX + CIN 2.9 +/- 0.6, SNX + S 3.0 +/- 0.7; sham + CIN 4.2 +/- 0.4, sham + S 4.5 +/- 0.4; sham pair-fed + CIN 3.3 +/- 0.5, sham pair-fed + S 3.5 +/- 0.6 cm/14 days; P = n.s.){There does seem to be a trend though for CIN reducing length thus suggesting that PTH may contribute to length}. Tibia length, the height of the total growth plate and the hypertrophic zone, OFA and chondrocyte proliferation rate were similar with CIN and S. Serum Ca(2+) declined with CIN treatment; PTH was 61% lower in CIN- compared to S-treated SNX. Food intake was similar, whereas body weight gain (21.6 +/- 8.7 versus 12.7 +/- 11.2 g) and body weight gain per food intake (141 +/- 50 versus 77 +/- 70 g/kg) improved in CIN- versus S-treated SNX animals."

"Exposure of rat metatarsal bones to the calcimimetic R-568 promotes chondrocyte proliferation and differentiation"

"Calcium influx is under the control of voltage-gated calcium channels. Blockade by verapamil dose dependently inhibits longitudinal bone growth, chondrocyte proliferation and differentiation in fetal rat metatarsalia cultures. Activation of the CaR also increases cytosolic calcium concentrations in chondrocytes by IP3-dependent calcium release from intracellular stores and by increased calcium influx into chondrocytes, and promotes chondrogenesis and bone growth "

Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor.

"The human parathyroid hormone type 2 receptor (PTH2R) is activated by PTH and by tuberoinfundibular peptide of 39 residues (TIP39), the latter likely acting as its natural ligand. Although the receptor is expressed at highest levels in the nervous system, we have observed that both PTH2R and TIP39 are expressed in the newborn mouse growth plate, with the receptor localizing in the resting zone and the ligand TIP39 localizing exclusively in prehypertrophic and hypertrophic chondrocytes. To address the role of PTH2R in postnatal skeletal growth and development, Col2a1-hPTH2R (PTH2R-Tg) transgenic mice were generated. The mice were viable and of nearly normal size at birth. Expression of the transgene in the growth plate was limited to chondrocytes. We found that chondrocyte proliferation was decreased, as determined by in vivo BrdU labeling of proliferating chondrocytes and CDK4 and p21 expression in the growth plate of Col2a1-hPTH2R transgenic mice. Similarly, the differentiation and maturation of chondrocytes was delayed, as characterized by decreased Sox9 expression and weaker immunostaining for the chondrocyte differentiation markers collagen type II and type X and proteoglycans. As well, there was altered expression of Gdf5, Wdr5, and β-catenin, factors implicated in chondrocyte maturation, proliferation, and differentiation.These effects impacted on the process of endochondral ossification, resulting in delayed formation of the secondary ossification center, and diminished trabecular bone volume."

"TH2R is expressed by chondrocytes in the resting/early proliferating zone, whereas TIP39 is expressed by prehypertrophic and hypertrophic chondrocytes. On the other hand, PTHrP is synthesized mainly by chondrocytes in the early proliferating zone, whereas PTH1R expression is concentrated in the prehypertrophic transition zone. Thus, the sites of expression of TIP39 and PTH2R are diametrically opposite of those of PTH1R and PTHrP. Although TIP39 expression is in proximity to PTH1R, this ligand is unlikely to interact productively with this receptor and in fact may function as an antagonist. Similarly, PTH2R, although it is 51% identical to PTH1R, would likely respond very poorly or fail to respond at all to PTHrP despite their close spatial proximity within the developing growth plate. "

"Wdr5 overexpression advances the timing whereas inactivation of Gdf5 signaling delays SOC formation"

"WDR5 represses β-catenin levels"

Regulation of PTHrP expression by cyclic mechanical strain in postnatal growth plate chondrocytes.

" In the growth plate, parathyroid hormone-related protein (PTHrP) regulates chondrocyte differentiation and longitudinal growth. Cyclic mechanical strain has been demonstrated to influence growth plate chondrocyte differentiation and metabolism. The objective of this study was to investigate whether short term cyclic tensile strain regulates PTHrP expression in postnatal growth plate chondrocytes in vitro and to explore whether the organization of cytoskeletal F-actin microfilaments is involved in this process. To this end, we obtained growth plate chondrocytes from 2-week-old Sprague-Dawley rats and sorted prehypertrophic and hypertrophic chondrocytes. The sorted chondrocytes were subjected to cyclic tensile strain of varying magnitude and duration at a frequency of 0.5 Hz. Cyclic strain regulates PTHrP expression in a magnitude- and time-dependent manner. Incubation of chondrocytes with cytochalasin D, an actin microfilament-disrupting reagent, blocked the induction of PTHrP expression in response to strain. Short-term cyclic tensile strain induces PTHrP expression in postnatal growth plate prehypertrophic and hypertrophic chondrocytes and that PTHrP expression by these chondrocytes may subsequently affect growth plate development. The organization of cytoskeletal F-actin microfilaments plays an important role in mechanotransduction."

"Targeted disruption of the PTHrP or PTHrP receptor genes leads to early cessation of chondrocyte proliferation and subsequent acceleration of premature hypertrophic differentiation. In contrast, mice overexpressing PTHrP develop short-limbed dwarfism and show a delay in endochondral ossification"

" articular chondrocytes showed remodeling of actin stress fibers in response to mechanical loading, including hydrostatic pressure, compressive strain and osmotic swelling"<-thus why there may need to be a deconditioning period with LSJL.

"actin filaments in human mesenchymal stem cells (hMSCs) became aligned perpendicularly to the axis of mechanical strain on an un-patterned elastic substrate when the cells were subjected to cyclic uniaxial strain within the physiological range (5% elongation, 1 Hz) for 2 days"

"There was no significant difference in PTHrP mRNA expression in chondrocytes strained at a magnitude of 1000 μstrain and unstrained control chondrocytes. However, PTHrP mRNA expression in chondrocytes strained at 2000 and 4000 μstrain was significantly higher than in unstrained chondrocytes"<-PTHrP levels were higher at 2000 than at 4000 microstrain.

"Application of strain for 1 or 6 h did not alter PTHrP protein levels in chondrocytes, while application of strain for 24 or 48 h significantly increased PTHrP protein expression in the chondrocytes"  mRNA levels were higher at 6 levels however.

Microstrain at the different levels did not affect the number of chondrocytes at each stage of the cell cycle however 4000 microstrain did increase the number of apoptotic chondrocytes.

" In strained chondrocytes, the actin fibers were oriented parallel to the long axis of the chondrocytes, and showed approximately perpendicular alignment with the direction of strain. However, in chondrocytes treated with CTS and in unstrained chondrocytes, pretreatment with cytochalasin D (1 μM) resulted in disruption of actin fiber organization and the formation of large focal actin aggregates"

"When the chondrocytes within the growth plate are sufficiently distal from the PTHrP-producing chondrocytes, the PTHrP concentration drops below a critical level and the chondrocytes in growth plate stop proliferating and begin to hypertrophy. The prehypertrophic and early hypertrophic chondrocytes liberate Ihh, which stimulates PTHrP synthesis and cell proliferation. In this way, PTHrP and Ihh together regulate the size of the growth plate proliferative zone and the rate of proliferation, and a negative feedback loop is thereby formed"

"application of 5% cyclic uniaxial strain (1 Hz) for 2 days increased human MSC proliferation and the relative number of cells in S phase and G2/M phases"

Effects of parathyroid hormone 1-34 on osteogenic and chondrogenic differentiation of human fracture haematoma-derived cells in vitro.

"progenitor cells with osteogenic and chondrogenic potential exist in human fracture haematoma, suggesting that the fracture haematoma-derived progenitor cells (HCs) contribute to fracture healing. However, there has been no study investigating the effect of PTH on HCs. We investigated the effect of pulsatile and continuous PTH treatment on human fracture HCs in vitro. HCs were isolated from seven patients. The HCs were divided into four groups: growth medium; control [osteogenic medium (OM) without PTH]; PTH-C (OM with continuous PTH); and PTH-P (OM with pulsatile PTH) groups. Osteogenic differentiation potential and proliferation of HCs were compared among the four groups. For chondrogenesis, the HCs were divided into two groups: control [chondrogenic medium (CM) without PTH]; and PTH-C (CM with continuous PTH) groups, and chondrogenic differentiation potential was analysed. PTH treatment did not affect cell proliferation, regardless of the mode of administration. Osteogenic activity was also not significantly affected by continuous PTH treatment but significantly inhibited by pulsatile PTH treatment. Conversely, chondrogenic differentiation was significantly inhibited by continuous PTH treatment. Our results revealed that PTH treatment on HCs, either continuous or pulsatile, does not exhibit any positive effect, and indicates that exogenous PTH administration after fracture has no effect on HCs. PTH may not have a positive effect at the fracture site during the early stage of fracture healing in which haematoma formation occurs."

"After 20 days of chondrogenic induction, HCs were successfully differentiated into chondrogenic cells."

Resting zone of the growth plate houses a unique class of skeletal stem cells

"Skeletal stem cells regulate bone growth and homeostasis by generating diverse cell types, including chondrocytes, osteoblasts and marrow stromal cells. The emerging concept postulates that there exists a distinct type of skeletal stem cell that is closely associated with the growth plate, which is a type of cartilaginous tissue that has critical roles in bone elongation. The resting zone maintains the growth plate by expressing parathyroid hormonerelated protein (PTHrP), which interacts with Indian hedgehog (Ihh) that is released from the hypertrophic zone, and provides a source of other chondrocytes. However, the identity of skeletal stem cells and how they are maintained in the growth plate are unknown. Here we show, in a mouse model, that skeletal stem cells are formed among PTHrP-positive chondrocytes within the resting zone of the postnatal growth plate. PTHrP-positive chondrocytes expressed a panel of markers for skeletal stem and progenitor cells, and uniquely possessed the properties of skeletal stem cells in cultured conditions. Cell-lineage analysis revealed that PTHrP-positive chondrocytes in the resting zone continued to form columnar chondrocytes in the long term; these chondrocytes underwent hypertrophy, and became osteoblasts and marrow stromal cells beneath the growth plate. Transit-amplifying chondrocytes in the proliferating zone—which was concertedly maintained by a forward signal from undifferentiated cells (PTHrP) and a reverse signal from hypertrophic cells (Ihh)—provided instructive cues to maintain the cell fates of PTHrP-positive chondrocytes in the resting zone. Our findings unravel a type of somatic stem cell that is initially unipotent and acquires multipotency at the post-mitotic stage, underscoring the malleable nature of the skeletal cell lineage. This system provides a model in which functionally dedicated stem cells and their niches are specified postnatally, and maintained throughout tissue growth by a tight feedback regulation system. "

" the resting zone of the growth plate houses a unique class of skeletal stem cells, the transit-amplifying progeny of which are lineage-restricted as chondrocytes that exhibit multipotency only at the post-mitotic stage "

According to Recapitulation of the Parathyroid HormoneRelated Peptide–Indian Hedgehog Pathway in the Regenerating Deer Antler Parathyroid is vital to the growth plate.