Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor

Maeda, Yukiko; Schipani, Ernestina; Densmore, Michael; Lanske, Beate

doi:10.1016/j.bone.2009.09.009

Cited by 34 publications

(24 citation statements)

References 22 publications

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“…Ihh is a critical factor secreted by chondrocytes, but its expression is restricted mainly to the hypertrophic zone (14). It is well known that increased activity of the Ihh signaling pathway promotes chondrocyte proliferation (57) and mutation or disruption of Ihh signaling results in reduction of the height of the columnar layer in the growth plate (58). GCs are also known to suppresses Hh activity in neurons (59).…”

Section: Discussionmentioning

confidence: 99%

Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

et al. 2019

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Glucocorticoids (GCs) are frequently used to treat chronic disorders in children, including inflammation and cancer. Prolonged treatment with GCs is well known to impair bone growth, an effect linked to increased apoptosis and suppressed proliferation in growth plate chondrocytes. We hypothesized that the endogenous antiapoptotic protein humanin (HN) may prevent these effects. Interestingly, GC‐induced bone growth impairment and chondrocyte apoptosis was prevented in HN overexpressing mice, HN‐treated wild‐type mice, and in HN‐treated cultured rat metatarsal bones. GC‐induced suppression of chondrocyte proliferation was also prevented by HN. Furthermore, GC treatment reduced Indian Hedgehog expression in growth plates of wild‐type mice but not in HN overexpressing mice or HN‐treated wild‐type animals. A Hedgehog (Hh) antagonist, vismodegib, was found to suppress the growth of cultured rat metatarsal bones, and this effect was also prevented by HN. Importantly, HN did not interfere with the desired anti‐inflammatory effects of GCs. We conclude that HN is a novel regulator of Hh signaling preventing GC‐induced bone growth impairment without interfering with desired effects of GCs. Our data may open for clinical studies exploring a new possible strategy to prevent GC‐induced bone growth impairment by cotreating with HN.—Zaman, F., Zhao, Y., Celvin, B., Mehta, H. H., Wan, J., Chrysis, D., Ohlsson, C, Fadeel, B., Cohen, P., Sävendahl, L. Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment. FASEB J. 33, 4962–4974 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

et al. 2019

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“…6,7). To study this disease in more detail, a transgenic mouse model expressing the H223R mutation under the control of the collagen ␣1(II) promoter, the Jansen mouse, has been generated (7,10,11). Interestingly, serum parathyroid hormone (PTH) levels are normal to low, distinguishing it from hyperparathyroidism (8,9).…”

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confidence: 99%

“…Interestingly, serum parathyroid hormone (PTH) levels are normal to low, distinguishing it from hyperparathyroidism (8,9). To study this disease in more detail, a transgenic mouse model expressing the H223R mutation under the control of the collagen ␣1(II) promoter, the Jansen mouse, has been generated (7,10,11). In both mice and humans, the mutant PTHR1 leads to cAMP accumulation, and thereby constitutive signaling, despite the absence of a ligand.…”

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confidence: 99%

Deletion of Zfp521 rescues the growth plate phenotype in a mouse model of Jansen metaphyseal chondrodysplasia

et al. 2011

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Jansen metaphyseal chondrodysplasia (JMC) is caused by a constitutively activating mutation of the parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor (PTHR1) and is characterized by widening of the metaphyses, reduction of long bone length, and short stature. A transgenic mouse expressing this mutation under the collagen α1(II) promoter has been generated to investigate the mechanisms responsible for this chondrodysplasia. We recently identified zinc finger protein 521 (Zfp521) as a downstream target gene of PTHrP signaling. Interestingly, loss of Zfp521 from chondrocytes leads to reduced cell proliferation and increased differentiation in the growth plate. Thus, we hypothesized that specifically ablating Zfp521 from Jansen chondrocytes could sufficiently rescue the chondrodysplasia phenotype. Our results show that Zfp521 expression is up-regulated in Jansen mouse growth plate chondrocytes and that PTHR1 is required for Zfp521 expression. Its ablation from Jansen chondrocytes restored normal cell differentiation, thus initiating chondrocyte apoptosis at the chondro-osseous junction, leading to partial rescue of endochondral bone formation shown by proper bone length. This study provides the first genetic evidence that Zfp521 is required downstream of PTHR1 signaling to act on chondrocyte proliferation, differentiation, and cell death.

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“…In this study, a conditional Ihh knockout mouse was generated that expressed a constitutively active PPR specifically in chondrocytes (Maeda et al, 2009). The authors showed that expression of the PPR was able to transiently maintain a growth plate.…”

Section: Discussionmentioning

confidence: 99%

PTHrP Treatment Fails to Rescue Bone Defects Caused by Hedgehog Pathway Inhibition in Young Mice

Brechbiel

Curran

2011

Toxicol Pathol

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The advent of molecular targeted therapies offers the hope of therapeutic advance in the fight against cancer. However, this hope is tempered by recent findings that certain targeted therapies may have unique side effects. The hedgehog (HH) pathway is a potential target for treatment of several cancers, including basal cell carcinoma (BCC) and a subset of medulloblastoma (MB). Recent clinical trials in adults have shown responses to HH pathway inhibition in both BCC and MB. However, concerns have been raised about the use of HH pathway inhibitors in children because of the role the HH pathway plays in development. Indeed, young mice treated with the HH pathway inhibitor, HhAntag, developed severe bone defects including premature differentiation of chondrocytes, thinning of cortical bone and fusion of the growth plate. In an effort to lessen the severity of bone defects caused by HhAntag, we treated young mice simultaneously with HhAntag and parathyroid hormone related protein (PTHrP), which functions downstream of Indian Hedgehog (IHH) to maintain chondrocytes in a proliferative state. The results show that while treatment with PTHrP causes a significant increase in trabecular bone, it does not prevent fusion of the growth plate induced by HhAntag.

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Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor

Cited by 34 publications

References 22 publications

Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

Deletion of Zfp521 rescues the growth plate phenotype in a mouse model of Jansen metaphyseal chondrodysplasia

PTHrP Treatment Fails to Rescue Bone Defects Caused by Hedgehog Pathway Inhibition in Young Mice

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