Interleukin-6 acts locally on the growth plate to impair bone growth

Fernandez-Vojvodich, Paola; Zaman, Farasat; Sävendahl, Lars

doi:10.1136/annrheumdis-2013-204112

Cited by 20 publications

(22 citation statements)

References 7 publications

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“…LPS is known to activate monocytes and macrophages involving TLR-4 and triggers the production of TNF-a (63), thereby up-regulating systemic inflammation. This is noteworthy, as our previous work has disclosed that both TNF-a and IL-6 suppress bone growth acting in synergy (29,64). Consequently, the anti-inflammatory effects of HNG could potentially alleviate bone growth impairment in patients with chronic inflammatory disorders.…”

Section: Discussionmentioning

confidence: 79%

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: 79%

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

et al. 2019

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“…A total of 14 patients with the DYRK1A mutation were reported, and all individuals shared congenital microcephaly at birth, intellectual disability, severe speech impairment, short stature, and distinct facial features. The association between high maternal serum level of IL-6 and impaired fetal growth was reported in vivo and in vitro 37. In this study, subjects 10A and 10B with profound short stature and compound heterozygous mutations in NBAS(MIM 608025)showed various anomalies, including facial dysmorphism, recurrent hepatitis, hypogammaglobulinemia, optic dystrophy, bone changes, and Pelger-Huët anomaly.…”

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confidence: 60%

“…The association between high maternal serum level of IL-6 and impaired fetal growth was reported in vivo and in vitro. 37 Tocilizumab, a humanized anti-IL-6R may be considered to increase bone growth in these patients. To date, NBAS deficiency has no cure or effective treatment, but thermal susceptibility to synthaxin-18 complex has been demonstrated, and aggressive fever control and fluid therapy may helpful in preventing a fatal course of acute liver failure.…”

Section: Discussionmentioning

confidence: 99%

High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing

et al. 2017

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“…However, little is known about the mechanism involving growth plate chondrocytes (Pass et al 2009. Generally, IL6 has been considered to act systemically suppressing growth by altering the GH/IGF1 axis, although more recent studies have shown that IL6 also has direct effects on the growth plate chondrocytes (Nakajima et al 2009, Fernandez-Vojvodich et al 2013.…”

Section: Impact Of Inflammation On Bone Growthmentioning

confidence: 99%

“…3c). However, the production of IL6 has been shown to significantly increase in fetal rat metatarsal bones after combined treatment with IL1b and TNFa (Fernandez-Vojvodich et al 2013;Fig. 5).…”

Section: Interactions Between Pro-inflammatory Cytokinesmentioning

confidence: 99%

RECENT RESEARCH ON THE GROWTH PLATE: Impact of inflammatory cytokines on longitudinal bone growth

Sederquist¹,

Fernandez-Vojvodich²,

Zaman³

et al. 2014

Journal of Molecular Endocrinology

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Children with inflammatory diseases usually display abnormal growth patterns as well as delayed puberty. This is a result of several factors related to the disease itself, such as malnutrition, hypercortisolism, and elevated levels of pro-inflammatory cytokines. These factors in combination with glucocorticoid treatment contribute to growth retardation during chronic inflammation by systemically affecting the major regulator of growth, the GH/IGF1 axis. However, recent studies have also shown evidence of a direct effect of these factors at the growth plate level. In conditions of chronic inflammation, pro-inflammatory cytokines are upregulated and released into the circulation. The most abundant of these, tumor necrosis factor a, interleukin 1b (IL1b), and IL6, are all known to directly act on growth plate cartilage to induce apoptosis and thereby suppress bone growth. Both clinical and experimental studies have shown that growth retardation can partly be rescued when these cytokines are blocked. Therefore, therapy modulating the local actions of these cytokines may be effective for preventing growth failure in patients with chronic inflammatory disorders. In this review, we report the current knowledge of inflammatory cytokines and their role in regulating bone growth.

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Interleukin-6 acts locally on the growth plate to impair bone growth

Cited by 20 publications

References 7 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

High diagnostic yield of clinically unidentifiable syndromic growth disorders by targeted exome sequencing

RECENT RESEARCH ON THE GROWTH PLATE: Impact of inflammatory cytokines on longitudinal bone growth

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