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In patients with thyroid eye disease (TED), pregnancy-associated plasma protein A (PAPP-A), a proteolyic enzyme, increases the levels of insulin-like growth factor (IGF); if PAPP-A expression is inhibited, IGF activity might also be decreased with less systemic side effects than other available medications.¹

With the intention of building off of this prior research, Cheryl A. Conover, PhD, of the Division of Endocrinology, Mayo Clinic, Rochester, Minn., and her colleagues proposed that using PAPP-A antibodies (Abs) to inhibit IGF factor I receptors (IGF-IRs) indirectly and more selectively would be effective in patients with TED.¹ Additionally, they sought evidence to validate the role that PAPP-A has in the pathogenesis of TED in order to propose novel therapies targeting the IGF axis. Their report was recently published online in The Journal of Clinical Endocrinology & Metabolism.

Assembling a cohort

Nineteen patients with TED were studied. Most had hyperthyroidism secondary to Graves disease; all of the patients had positive thyroid-stimulating hormone (TSH) receptor Abs and/or thyroid-stimulating immunoglobulin.¹ The tissue studied was obtained from orbital decompression surgery, which was performed for 1 of the following 4 reasons: 52.6% (n=10) had proptosis reduction for exposure pathology (in patients with inactive disease), 26.3% (n=5) had compressive optic neuropathy, 15.8% (n=3) had proptosis reduction with inflammation that didn鈥檛 respond to medical treatment, and 5.3% (n=1) had globe subluxation. The median excess proptosis value before decompression was 5 mm.

TNF-伪 and IL-1尾 are proinflammatory cytokines that are increased in the orbital tissue of patients with TED and stimulate PAPP-A expression.¹ As such, in the 19 patients with TED, IL-1尾, TNF-伪, and IL-6 (with IL-6 receptor) were used to treat the primary isolated orbital fibroblasts in the laboratory. After 24 hours, RNA was isolated by reverse transcription quantitative polymerase chain reaction. Dr. Conover and her co-authors found that PAPP-A expression increased approximately fourfold with treatment with IL-1尾 and TNF-伪 (P < .0001). Additionally, PAPP-A was just as active as an IGF-dependent protease. In the cluster of differentiation (CD) subsets, CD34+ fibroblasts comprised the vast majority of the fibroblasts from TED cultures. CD34+ fibroblasts represent 80% of the fibroblasts in TED and secrete 70% of PAPP-A expressed.¹

Inhibitory PAPP-A antibodies decreased IGF-I activity

Looking at the effect of PAPP-A inhibition on IGF-IR activation, the investigators found that cell proliferation, differentiation, and survival were mediated by IGF-I stimulation of the phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway. In addition, increased phosphorylated (p)Akt was a sign that IGF-I/IGF binding protein (BP)-4 stimulated鈥揑GF-IR activation of the PI3K/Akt pathway was enhanced by TNF-伪-induced PAPP-A expression in the TED fibroblasts. The IGF-I鈥檚 effects on receptor activation were decreased by inhibitory mAb-PA1/41 by 53 卤 4% (P < .0001).

In summary, the investigators found that orbital fibroblasts from patients with TED: 

• Express and secrete proteolytically active PAPP-A.
• Had significantly increased PAPP-A mRNA and protein expression with IL-1尾 and TNF-伪 treatment.
• Did not have a change in IGF-IR mRNA expression.
• Had suppressed IGF-IR activation secondary to inhibition of PAPP-A鈥檚 proteolytic activity.

These data supported the investigators鈥� hypotheses that, in their words, 鈥淧APP-A plays a significant role in promoting TED and that targeted inhibition of PAPP-A could be a therapeutic option or adjuvant.鈥�¹

Benefits of zeroing in on PAPP-A proteolytic activity

The authors discussed several advantages of targeting PAPP-A proteolytic activity, including the following:

• It鈥檚 specific due to its unique amino acid sequence.
• Because it is secreted and associated with the extracellular surface of cells, it is able to be targeted by drugs. 
• It is selective because it is cell-specific. 
• Moderate restraint of IGF signaling would occur because of its inhibition.
• The adverse effects were likely to be minimal because, in animal studies, mice with a PAPP-A gene deletion had long lives and no secondary endocrine or metabolic dysfunction.

Limitations and conclusions

Dr. Conover and her co-authors mentioned a few limitations of their study, including its small sample size. Additionally, there are inherent limitations to cell culture in terms of not being able to recreate the interactive processes occurring in vivo. Lastly, the authors didn鈥檛 look directly at the effects of PAPP-A/IGF in TED fibroblasts on regulation of hydrophilic glycosaminoglycan production.

These limitations aside, the investigators concluded that 鈥�. . . these data indicate that proinflammatory cytokines in the orbital tissue of TED stimulate CD34+ fibroblasts to express and secrete proteolytically active PAPP-A that enhances local IGF-IR activity. This activity could be inhibited by a specific monoclonal antibody that inhibits PAPP-A鈥搈ediated IGFBP-4 proteolysis. Thus, these results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis.鈥�¹

Published: July 30, 2024