Department of Biotechnology
All India Institute of Medical Sciences (AIIMS)
New Delhi -110029, India
Translational Immunology, Osteoimmunology & Immunoporosis Lab
(TIOIL)
The birth place of "Immunoporosis" : Immunology of Osteoporosis
Dr. Rupesh K. Srivastava
PhD, MBA
Welcome to Translational Immunology, Osteoimmunology & Immunoporosis Lab group at AIIMS, New Delhi. During my doctoral research work form NCCS, Pune I got a glimpse of the very exciting and thrilling field of Immunology. This led me to further continue my research work in the field of Bone and Immunology at Columbia University Medical Centre, NY, USA and Roswell Park Cancer Institute (RPCI), New York, USA. After coming back to India in 2013 as an Assistant professor at Central University, Sagar (MP), and now at All India Institute of Medical Sciences (AIIMS), New Delhi, I am actively involved in deciphering this new field which is still in its very naive state. My research specifically focuses on the cellular and molecular interactions between the Immune and Bone systems i.e “Osteoimmunology” (Frontiers in Biosciences, 2018), a very recent branch of modern biology which specifically deals with the interplay between the immune cells (CD4, CD8 T cells, B cells, DCs, Macrophages, ILCs etc.) and bone cells (Osteoclast, Osteoblast & Osteocytes). During normal physiology both systems are at homeostasis but during an imbalance due to various stimuli (infection, autoimmunity, environment, ageing, hormones etc.), it leads to various inflammatory conditions such as Osteoarthritis, Rheumatoid Arthritis & Osteoporosis (viz. post-menopausal osteoporosis). Thus, a molecular understanding of these interactions is at the heart of my research which would ultimately lead to discovery of novel therapeutics for various inflammatory bone conditions.
My Lab is currently involved in the following areas of medical research:
I. “Immunoporosis”: Immunopathophysiology of Osteoporosis
One of the key bone diseases associated with aging and postmenopausal condition is osteoporosis which affects more than 200 million individuals worldwide. Menopause is a major risk factor for osteoporosis. Osteoporosis is termed as a “Silent Killer” because bone loss occurs without symptoms and in many cases, the first "symptom" is a broken bone itself. The worldwide cost burden of osteoporosis (for all ages) is forecasted to increase to USD 131.5 billion by 2050. In fact, fifty percent of the women population over the age of 50 will experience an osteoporosis-related fracture in their lifetime. Also, there is elevated risk of wrist, hip, or spine fracture due to osteoporosis which is estimated to be parallel to the risk of heart disease. In women’s over age of 45, osteoporosis accounts for more days spent in hospital than diabetes, heart and cancer taken together.
Osteoporosis or enhanced bone loss is affected by various environmental factors including sex, diet, age, toxins etc. Our group for the first time clearly highlighted and summarized the specific role of immune system in the development and pathophysiology of post-menopausal osteoporosis leading to establishment of a new field of biology proposed by me as “Immunoporosis: The Immunology of Osteoporosis” with special emphasis on the role of both Innate and Adaptive immune system in pathophysiology of Osteoporosis (Frontiers in Immunology, 2018; PNAS-India, 2021 & J. of Inflammation Research, 2022).
II. Pioneers in discovering the “anti-Osteoclastogenic” role of regulatory B cells (Bregs) in Osteoporosis”
We are pioneers in establishing that regulatory B cells (Bregs) viz. CD19+IL-10+ and CD19+CD1dhiCD5+IL-10+ Bregs exhibit anti-osteoclastogenic potential. Moreover, we for the first time reported that reduction in Bregs number observed in osteoporotic mice model is one of the prime contributing factors towards inflammatory bone loss observed in osteoporosis (Frontiers in Immunology, 2021 & 2022). These results of ours thus provide novel insight into Bregs biology in the context of osteoporosis. Moreover, apart from these Bregs population, we also observed that other Bregs population with characteristic phenotypes of CD19+FOXP3+ Bregs and CD19+CD11b+ Bregs are also found to be decreased in case of osteoporotic mice model. Thus, further studies are need of the hour to fully dissect and establish the role of various population of Bregs in post-menopausal osteoporotic conditions which would thereby lead towards future employment of Bregs based cellular therapy in ameliorating inflammatory bone loss observed in osteoporosis.
III. Pioneers in Discovering the “Osteoclastogenic” potential of Th9 cells in Osteoporosis”
We are pioneers in establishing that Th9 cells exhibit osteoclastogenic potential. We for the first time revealed that estrogen diminishes the potential of Th9 cells to produce IL-9 (JBMR Plus, 2024). Th9 cells in an IL-9-dependent manner enhance osteoclastogenesis and thus could establish themselves as a novel osteoclastogenic Th cell subset. We identify IL-9-secreting Th9 cells as a driver of bone loss with attendant modulation of the gut-immune-bone axis, which implies IL-9-targeted immunotherapies as a potential strategy for the management and treatment of inflammatory bone loss observed in post-menopausal osteoporosis.
IV. “Osteobiotics”, “Osteomicrobiology”, “Osteometabolism” & “Osteonutrition”
Our group is at the forefront in therapeutically managing bone loss in post-menopausal osteoporotic mice model via dietary changes i.e. “Osteonutrition”-salt and sugar intake, food preservatives etc. (Scientific Reports, 2018) along with identifying various probiotic strains for enhancing bone health a field called as “Osteomicrobiology” (Bone Reports, 2018; Nutrition, 2018, Scientific Reports, 2021 & Frontiers in Microbiology, 2022). My group is involved in dissecting the role of Probiotics on Bone health viz. post-menopausal osteoporosis in ovx mice model. The GM interacts with the host immune system (a two-way communication) thereby providing various beneficial effects on the host. Our group is interested in the novel role of probiotics in regulating bone health through its effect on the host immune system. Osteo-microbiology thus is a perfect integration of three independent fields of biology and thus future research on the same will be of immense clinical importance and will benefit people by providing a novel treatment option to various inflammatory conditions including post-menopausal osteoporosis. We are pioneer in this field of biology in India and have got novel findings in the field. Exciting initial results (published and unpublished) in our lab had suggested a strong positive interaction between the gut microbiota + Immune system + bone System (= Osteomicrobiology). Our results for the first time demonstrate that administration of specific probiotic strains such as Lactobacillus acidophilus (Bone Reports, 2018); Bacillus clausii (Nutrition, 2018); Lactobacillus rahmnosus (Scientific Reports, 2021) and Bifidobacterium longum (Frontiers in Immunology, 2022) inhibits ovx-induced post-menopausal osteoporosis in mice by modulating host immune system thereby validating the use of probiotics as possible novel therapeutics in treatment of post-menopausal osteoporosis, RA and various other inflammatory diseases; a field now called by us as “OsteoBiotics” i.e. role of Biotics in Bone Health.
We are further emphasizing on the role of GUT-associated metabolites (GAMs) such as short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), indole derivates, bile acids, etc., in regulating the energetics of bone cells and their plausible role in maintaining bone health. Emphasis is importantly placed on highlighting knowledge gaps in this novel field of skeletal biology, i.e., “Osteometabolism” (proposed by our group) (Cells, 2022; Journal of Biological Macromolecules, 2024) that need to be further explored to characterize the physiological importance of skeletal cell bioenergetics in the context of human health and bone related metabolic diseases.
V. Extracellular Vesicles (EVs) and Bone Health
Studies have shown that an impaired bone remodeling cycle in osteoporosis leads to dysregulated EV secretion from bone cells that may further aggravate the disease progression. Thus, we are dissecting the role of EVs in osteoporosis under both preclinical and clinical conditions (Serum derived EVs). This would not only benefit osteoporotic patients in the postmenopausal period, but also those suffering from other bone diseases.
VI. “Osteo-Therapeutics”: AYUSH Based Therapies
Extensive safety concerns are of utmost importance with treatment, as presently accessible drugs (strontium, bisphosphonates and estrogen-replacement-therapy) in treating osteoporosis are associated with several undesirable effects. My group is involved in comprehensively identifying novel plants and their phytoconstituents with potent osteoprotective properties. We further are actively engaged into identifying and developing various novel Phyto-therapeutics for treatment and management of Osteoporosis. We have identified 40 such plants with osteoprotective properties (Frontiers in Bioscience, 2020). We have already published and established the anti-osteoporotic properties of Cissus quadrangularis (Hadjod, Cells, 2023), Moringa oleifera (Drumstick) and Crocus sativus (Saffron, Phytomedicine Plus, 2022) in mice. Thus, a molecular insight into this novel field of biology would thus leads to development of innovative approaches for the prevention and treatment of post-menopausal osteoporosis and other bone pathologies.
Despite its efficacy in preventing osteoporosis, homeopathy remains one of the most controversial subjects in therapeutics. The reason is the lack of scientific evidence in support of homeopathy. There are few peer reviewed papers that have shown the role of homeopathic remedies in management of osteoporosis. Therefore, in taking note of the exigent need of basic studies for establishing the efficacy of homeopathic remedies in osteoporosis, we, are performing well-planned scientifically validated studies to delineate the role of selected homeopathic formulations (SHFs) in treatment of osteoporosis under in vitro, in vivo and ex vivo conditions.
VII. Glucocorticoid-induced Osteoporosis (GIOP)
Glucocorticoids (GC) are anti-inflammatory drugs prescribed for several inflammatory disorders, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), asthma, etc. Fractures occur in 30–50% of people on long-term GCs. Even though GCs effectively relieve symptoms and reduce inflammation, long-term usage of GCs can have substantial side effects, such as osteoporosis (GIOP). Even small doses of GCs can increase the risk of fractures. GIOP is documented as the primary cause of secondary osteoporosis. GIOP causes increased morbidity and mortality and dramatically raises the risk of osteoporosis-related fractures in long-term GC users. The currently available treatments for GIOP are denosumab, bisphosphonate, etc. Despite their effectiveness, these interventions have several side effects. As a result, novel therapeutic strategies are required for GIOP management and prevention. Our group has shown the efficacy of probiotics to dampen the inflammatory milieu under PMO. However, the role of probiotics in alleviating GIOP is limited to very few studies. Moreover, the immunopathogenesis of GIOP is unknown and the role of probiotics in ameliorating GIOP via modulation of the immune system is a completely untouched area. We therefore are investigating the possible nexus between the immune system, gut microbiota (GM), and GIOP. Our work will be beneficial for millions of people who are using GCs for several reasons including the long COVID-19 patients in which bone loss is evidenced by recent studies.
We are also further exploring the role of immune system in the fracture and in the progression of osteoarthritis
VIII. Osteoarthritis (OA)
After establishing the role of the immune system in Osteoporosis we are further delineating the nexus between the immune system and the pathogenesis of OA by developing the destabilization of the medial meniscus (DMM) mouse model. The DMM mouse model is a widely used surgical model in osteoarthritis research to study the progression and mechanisms of the degenerative joint disease that affects the cartilage and underlying bone of joints.
IX. Osteosarcoma
The presence of osteosarcoma and its metastatic lesions can alter the metabolic landscape of CD8+ T cells. The tumor microenvironment (TME) often exhibits low nutrient availability and high levels of immunosuppressive factors, which can lead to metabolic dysfunction in T cells (Bone Reports, 2024). We are analyzing the metabolic pathways active in CD8+ T cells within the TME of osteosarcoma, providing insights into how these pathways are altered during metastasis. It has been observed that the outcome of patients regarding available anti-tumorigenic therapies is poor and patients respond differently to the same therapy due to differing gut microbiota composition. The “gut-bone-immune” axis has been well developed and gut microbiota and its metabolites are important in maintaining bone health. ILA (indole-3-lactic acid, gut-associated metabolites-GAM) has been observed to reverse the CD8+ T cell exhaustion and enhance their metabolic status. Thus, we are further investigating the role of GAMs in preventing osteosarcoma progression via modulating the CD8+T cell metabolism.
X. “Osteo-toxicology & Osteo-metabolism”
We are pioneer in dissecting the effect of various environmental pollutants (Cyanotoxins, Particulate Matter-PM etc.) on the Osteoimmune system with immense future implications in the field, a point of major concern with increase in worldwide pollution on all fronts. Cyanobacteria (CB) represent group of photoautotrophic bacteria’s occurring in fresh as well in brackish water bodies. Chronic or repeated exposure to low cyanotoxin levels is one of most important factors affecting human health in general. Different cyanobacteria toxins have been implicated with serious health issues worldwide due to the production of various bioactive and toxic metabolites especially microcystins (MCs). According to World Health Organization (WHO) 1𝜇g/L of MC-LR is admissible, but the concentration of microcystins in present day water bodies is many times beyond the recommended guidelines. We for the first time have demonstrated the direct effect of MC-LR on bone health via affecting the host osteo-immune system (Environmental Pollution, 2018). Our study thus highlights the risk associated with intake of contaminated water and food not only to our immune system but also to our bones establishing a direct link between MC-LR intake and enhanced bone loss. Our study for the first time have established a direct link between the intake of cyanotoxin viz. MC-LR (a WHO categorized carcinogen, present in all water bodies) and enhanced bone loss thereby giving a strong impetus to the naïve field of “Osteo-toxicology”, a termed coined by my group.
XI. “Osteofertility”
Recent advances have dramatically increased our understanding of how organ system works through different physiologies to regulate a function. Bone-health is already reported to be linked with male-reproductive health, also recent study from our lab (Scientific Reports, 2018; Reproductive Sciences, 2023), had established the role of high dietary salt (HSD) intake in regulating bone-health via its effect on host osteo-immune system. Therefore, we are next asking the question: what is the link between dietary-salt-intake and male fertility? Leading to birth of a novel scientific discipline coined by our group as “Osteofertility”. Also, no study till date had ever-linked the negative effects of dietary-salt-intake on male fertility. We thus are actively involved in dissecting the role of dietary-salt-intake on male-fertility via modulation of complex interplay between host “Immune-Bone-Testis” axis. Having proven the undesired effect of dietary-salt on male fertility, it will be of immense clinical importance for those affected with infertility as dietary factors have proven combinatorial role in manifesting fertility related problems. We already have interesting unpublished data about the negative effects of HSD on male fertility. Establishing a direct link between dietary-salt-intake and male fertility will be of immense clinical importance for managing fertility disorders in males. Thus, dietary cut down of salt intake may play an important role in managing fertility. Moreover, the present study would associate that dietary salt not only effects bone loss but at the same time also modulates fertility in males. The results of this study will establish dietary modulation of salt intake as a viable treatment/management option in male reproductive health thereby combating the increasing fertility problems of the country. The present study would pave a path towards a better understanding of the intricate relationship between diet and Osteofertility.
XII. Research in “Immunology of COVID-19, Uveitis, ARDS & Sepsis” and its effect on Bone Health”
We are exploring the Immunology of COVID-19 with emphasis on managing Cytokine Storm induced by COVID-19 via both Biotics and Phytotherapeutic interventions (International Reviews of Immunology, 2021; Frontiers in Bioscience, 2021; Exploration in Immunology, 2023) and Uveitis (Immunology Letters, 2024). Moving ahead recently we have established the prophylactic role of LR and its associated metabolites (Butyrate) in the prevention and management of both pulmonary and extrapulmonary (Sepsis) ARDS via targeting neutrophils (Clinical Immunology, 2024). Lastly, we are further looking into the implications of long-COVID, ARDS and Sepsis on Bone Health (Inflammation Research, 2022).
XIII. Artificial Intelligence, Machine Learning, Osteo-Informatics and Osteo-Omics
It is anticipated that machine learning and artificial intelligence will instigate the development of clinical interventions for osteoporosis. We believe that this approach holds great promise for the future of bone research (Giuffrè et al., 2023). With the standardization of protocols, these strategies hold the potential to revolutionize the management of bone pathologies. Diverging from conventional research paradigms that often focus on singular aspects, this novel approach will help in designing several immunotherapies for osteoporosis. Therefore, we are exploring artificial intelligence and machine learning approaches for designing suitable personalized immunotherapies for the treatment and management of osteoporosis.
COLLABORATIONS
