Sclerostin Vaccine Prevents Osteoporosis

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Osteoporosis tops the cause of chronic bone abnormality, putting the skeleton at a risk of fracture due to severely low bone mass and terribly fragile architecture, and affecting over fifty million people around the world [1]. This degenerative bone disorder takes place with age and turns patients’ activity and life quality upside down. Most devastatingly, postmenopausal women and the elderly have osteoporotic fracture problems may be confined to bed for a long while or even lose independence in the aftermath.

Dealing with the osteoporosis-associated comorbidities has become a huge healthcare expenditure drain and a socioeconomic burden in developed countries (over €700 million) [2]. With respect to anti-osteoporosis remedies, vitamin D supplements and bisphosphonate are common prescriptions. Biological agents targeting specific molecules in bone tissue, like parathyroid hormones, vitamin K inhibitor, and certain monoclonal antibodies are emerging medications [3].

The fact is that healthy bone is dynamically orchestrated by bone formation and resorption reactions. Bone-forming cells, namely osteoblasts and osteocytes, produce proteins to pile up mineralized matrices, bone-resorbing cells, i.e. osteoclasts, which coordinately remodel microstructure inside the skeleton. Once bone resorption exceeds formation, the skeletal component is progressively eaten away, the well-woven network within bone is ultimately broken down into a porous structure [4]. In this sense, thinking out therapeutics specifically getting rid of the substances adverse to bone tissue for dragging osteoporosis progression is largely demanding.

Of the proteins, bone cells secrete, Wnt and sclerostin (SOST) have different effects on bone-forming cells. The former is indispensable in maintaining bone formation activity, whereas the latter is detrimental to bone tissue by antagonizing Wnt function [5]. In view of the SOST blockade beneficial for bone mass and broken bone repair, we came up with the idea to develop a SOST vaccine for neutralizing endogenous SOST to prevent osteoporosis.

To this end, with gene recombination and protein engineering approaches, we picked a SOST gene sequence coding a peptide specifically targeting Wnt and engineered it with a gene sequence coding immunoglobin Fc fragment to produce a SOST-Fc fusion protein. We anticipated the immunoglobin Fc fragment enhancing immunogenicity of SOST peptide in vivo. Upon confirming SOST specificity the engineered peptide contained, SOST-Fc was injected into mice to boost anti-SOST antibody in blood. Of interest, it caused 4.1-fold increases in serum anti-SOST antibody levels along with 32% reduction in serum SOST concentrations. SOST-Fc vaccine shot is safe because animals’ general physiology, like body weight gain, activity, cardiac, renal and liver functions, and hematology, stay normal. In addition, the anti-SOST serum did neutralize the adverse effect of SOST as it was added to SOST protein-treated bone forming cells.

Next, we tested whether SOST-Fc vaccine prevented osteoporosis. We utilized bilaterally ovariectomized mice to simulate a menopausal osteoporosis model. SOST-Fc vaccination significantly restored bone formation markers and reduced bone resorption products in serum fractions — a hint that bone tissue actively responded to the remedy. Strikingly, arrays of μCT imaging analysis and biomechanical tests revealed that SOST-Fc vaccine compromised the severity of bone mineral density loss, microarchitecture porosity, and biomechanical property irregularity of skeletons in ovariectomized mice. The osteoporosis histopathology, like abundant osteoclast formation, decreased bone mineral deposition, and fatty marrow were also alleviated after SOST-Fc vaccination. We also figured out what the molecular event going on behind this vaccine protection from osteoporosis was, showing that Wnt function in bone tissue was improved after vaccination.

Having a good lifestyle, like a nutritious diet, regular exercise, mild sunbathing, and stopping smoking, etc., makes bones stay strong. Vaccination may empower our body to produce immunity to shield bone tissue off osteoporosis. Profound evidence from this study underpins the idea that SOST-Fc vaccine is an effective therapeutic potential to ward off excessive bone loss. This innovative invention is the first step to use a new SOST immunotherapy for improving menopausal osteoporosis. It also paves the way undergoing to evaluate its long-term effects on bone loss. We also highlight a perspective of SOST-Fc vaccine to compromise various types of osteoporotic disorders, like age-related, glucocorticoid excess-, and inherited osteogenesis imperfecta, etc.

These findings are described in the article entitled Sclerostin vaccination mitigates estrogen deficiency induction of bone mass loss and microstructure deterioration, recently published in the journal Bone. This work was conducted by Feng-Sheng Wang, Re-Wen Wu, Wei-Shiung Lain, Tsai-Chen Tsai, Yu-Shan Chen, Yi-Chih Sun, Huei-Jing Ke, Jui-Chen Li, and Jih-Yang Ko from Kaohsiung Chang Gung Memorial Hospital, Taiwan, and Jaulang Hwang from Academia Sinica, Taiwan.

References:

  1. Black DM, Rosen CJ. Clinical Practice. Postmenopausal osteoporosis. N Engl J Med 2016;374:254-262.
  2. Jonsson E, Hansson-Hedblom A, Ljunggren Ö, Åkesson K, Spångeus A. Kanis JA, Borgström F. A health economic simulation model for clinical management of osteoporosis. Osteoporosis Int 2018;29:545-555.
  3. Khosla S, Hofbauer LC. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol 2017;5:898-907.
  4. Hendrickx G, Boudin E, Van Hul W. A look behind the scenes: the risk and pathogenesis of primary osteoporosis. Nat Rev Rheumatol 2015;11:462-474.
  5. Ke HZRichards WGLi XOminsky MS. Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev 2012;33:747-783
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