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CHARACTERIZATION OF SERPINA1 IN ADULT SPINAL HOMEOSTASIS TO INFORM TREATMENT STRATEGIES

thesis
posted on 2023-12-07, 16:42 authored by Neharika BhadouriaNeharika Bhadouria

People suffering from COPD are also known to suffer from other musculoskeletal issues like fracture risk, back pain, etc. Intervertebral disc degeneration (IVD) is a prominent cause of back pain and inflammation, influenced by factors such as aging, sudden loading, and genetics. SERPINA1, a common genetic variant in individuals with chronic obstructive pulmonary disease (COPD), encodes the alpha-antitrypsin protein (AAT). AAT deficiency is also associated with IVD degeneration, bone loss, and gait impairment. Currently, AAT-deficient individuals receive costly and short-lived weekly AAT injections, with no established guidelines for managing IVD degeneration and osteoporosis. Our primary research objective was to examine the effects of serpinA1a/c using a mouse model with global knockout (KO) of serpinA1a/c, generated through CRISPR technology, on intervertebral discs (IVD) and bone. We found that global deletion of serpinA1a/c was found to cause IVD elastin degradation, leading to a loss of mechanical properties. Moreover, serpinA1 was associated with increased bone-resorbing cells (osteoclasts) and a reduction in bone-forming cells (osteoblasts). Notably, sexual dimorphism was observed, with female IVDs exhibiting less degeneration than male counterparts, and serpinA1a/c KO mice were protected from mechanically-induced tail compression. Even in human IVDs, males expressed more AAT-1 compared to female IVDs. There are no FDA-approved drugs currently existing for IVD degeneration. Since IVD degeneration frequently occurs in individuals with osteoporosis, it shows a probable cross-talk happening between IVD and bone. In our study, we found the association of serpinA1 with estrogen receptor alpha and osteoclasts. Hence, we investigated the potential of raloxifene, an FDA-approved selective estrogen receptor modulator (SERM) typically prescribed to post-menopausal women for osteoporosis treatment, in averting IVD degeneration and improving mechanical characteristics in IVD. Our findings suggest that raloxifene injection may retard IVD degeneration induced by AAT deficiency, particularly in male mice. Furthermore, the latter study touched upon a conditional serpinA1a mouse model crossed with aggrecan-cre, specifically targeting serpinA1a-expressing cells in the IVD while sparing bone. Conditional serpinA1a deletion induced mild IVD degeneration without affecting bone loss. In summary, this study serves as a foundation for testing potential treatments for AAT patients with IVD degeneration and osteoporosis. It also provides compelling evidence for considering raloxifene as a treatment option for IVD degeneration in AAT-deficient patients experiencing IVD-related pain.

History

Degree Type

  • Doctor of Philosophy

Department

  • Mechanical Engineering

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Dr. Nilsson Holguin

Advisor/Supervisor/Committee co-chair

Dr. Adrian Buganza- Tepole

Additional Committee Member 2

Dr. Joseph M. Wallace

Additional Committee Member 3

Dr. Thomas H Siegmund