Research

We are interested in studying the cellular and molecular pathophysiology of interactions between bone and immune systems in important autoimmune and musculoskeletal diseases. We also working in the area of stem cell biology and regenerative medicine.

Bone contains two distinct cell types, the osteoclasts, essential for bone resorption (break-down) and the osteoblasts, essential for bone formation (synthesis). Osteoclasts differentiate from hematopoietic precursors of monocyte/macrophage lineage and osteoblasts differentiate from mesenchymal stem cells. The co-ordinated activity of osteoclasts and osteoblasts is essential to maintain the bone homeostasis in musculoskeletal and autoimmune diseases. Pathological bone loss is caused by increase in number and activity of osteoclasts; and also, by decrease in number, activity and life span of osteoblasts. It is further aggravated by activated T lymphocytes and several pro-inflammatory cytokines. Thus, the regenerating potential of adult bone and cartilage is limited in autoimmune and musculoskeletal diseases. The present treatment prevents only the partial bone/cartilage loss and does not enhance/induce their regeneration. Therefore, to completely understand the disease pathogenesis and develop the better therapeutics strategies for these diseases, it is very important to understand the regulation of bone and cartilage remodeling at physiological, cellular and molecular levels.

We are doing multidisciplinary research to understand the regulation of cellular and molecular pathophysiology of osteoporosis, osteoarthritis and rheumatoid arthritis. My group has made significant and innovative research contributions in identifying the novel role of interleukin-3 (IL- 3), a cytokines secreted by T lymphocytes, as an anti-inflammatory, immune-modulatory, anti-osteoclastic molecule and as a stimulator of tissue regeneration. We demonstrated for the first time that IL-3 prevents pathological bone loss induced by several pro-inflammatory cytokines and also stimulates new bone and cartilage regeneration and induce immune tolerance.

• We revealed for the first time that IL-3 acts directly on mouse osteoclast precursors, and inhibits RANKL (receptor activator of NF-κB ligand, an osteoclast differentiation factor)-induced osteoclast differentiation and diverts the cells to macrophage lineage (Khapli et al. 2003, The Journal of Immunology 171:142-151).
• TNF-α is crucial to the pathogenesis of osteoporosis, and bone and joint destructions in rheumatoid arthritis. We further demonstrated that IL-3 also inhibits TNF-α-induced osteoclast differentiation inhibits the surface expression of both c-Fms and TNF receptors 1 and 2 (Yogesha et al., 2005, Journal of Biological Chemistry 280:11759-11769).
• We then revealed that IL-3 inhibits TNF-α-induced bone resorption in presence of many proinflammatory cytokines including IL-1α, TGF-β1, TGF- β3, IL-6 and PGE2. IL-3 prevented TNF-α-induced c-fos nuclear translocation, and AP-1 activation. Interestingly, IL-3 prevents the development of inflammatory arthritis in mice, and protects cartilage and bone destruction [Yogesha et al, 2009, The Journal of Immunology 182: 361-370). Our these novel findings were highlighted in Research Highlight Section of Nature Reviews Rheumatology 2009 5:180 journal.
• This study was further extended to human osteoclast differentiation and bone resorption. Interestingly, we found that IL-3 also inhibits human osteoclast differentiation and bone resorption and diverts the cells to dendritic cell lineage. Moreover, IL-3 inhibits bone resorption in osteoclast precursors isolated from osteoporotic individuals (Gupta et al., 2010 The Journal of Immunology 185:2261-2272).
• Importantly, IL-3 helps in restoring the decreased RANKL/OPG (osteoprotegerin) ratio in vivo in mice, which is observed in important skeletal disorders (Singh et al., 2018, The Journal of Immunology 200:595-606).

B) Immunomodulatory role of IL-3 in regulating the pathophysiology of autoimmune diseases

• We developed the animal model of human rheumatoid arthritis, which was used for both fundamental and translational research; and also, for stem cell therapy and regenerative medicine.
• In mouse model of rheumatoid arthritis, we demonstrated that IL-3 attenuates collagen-induced arthritis by modulating the development of Foxp3+ regulatory T (Treg) cells in thymus, lymph nodes, and spleen. IL-3 decreases the production of proinflammatory cytokines IL-6, IL-17A, TNF-a, and IL-1 and increases the production of anti-inflammatory cytokines IFN-g and IL-10 in mice (Srivastava et al., The Journal of Immunology. 2011, 186:2262-2272).
• Recently, we observed that IL-3 inhibits the development of pathogenic Th17 cells and increases the number of Treg cells in IL-2-dependent manner and ameliorates collagen-induced arthritis in mouse model of human rheumatoid arthritis (The European Journal of Immunology-manuscript has come for the revison).
• Recently, we investigated that the expression of IL-3R on T helper cells is modulated by IL-4; and IL-3 regulates the development and effector function of Th2 cells (Kumar et al., 2020, The Journal of Immunology 204: 819-831). Our results strongly suggest that IL-3 has important immunomodulatory role in regulation of pathophysiology of rheumatoid arthritis.

C) Tissue regenerative potential of IL-3

• In osteoporosis and rheumatoid arthritis osteoblast number is decreased and these cells are defective in synthesis of bone matrix. Therefore, the regenerative potential of bone is poor in many bone diseases. In further investigation we found that IL-3 increases osteoblast differentiation and bone mineralization from human mesenchymal stem cells (MSCs) in both in vitro and in vivo conditions (Barhanpurkar et al., 2012, Biochem Biophys Res Commun. 418:669-75).
• Healing of bone damage or regeneration of new bone requires recruitment of MSCs with increased potential of osteoblast differentiation and bone formation. Interestingly, IL-3 enhances the migration and wound healing abilities of MSCs in both in vitro and in vivo conditions. These results indicates that IL-3 play a dual role in inducing differentiation of MSCs into osteoblasts and migration of MSCs towards the site of bone damage (Barhanpurkar-Naik et al. 2017 Stem Cell Research and Therapy 8:168:1-15).
• In osteoarthritis both cartilage and subchondral bone are affected. Our studies provided further evidence that IL-3 ameliorate degeneration of both articular cartilage and subchondral bone in osteoarthritic mice and also prevent in vitro degeneration of human cartilage differentiated from stem cells (Kour et al., 2016 The Journal of Immunology 196:5024-35). These findings are also highlighted by Nature Reviews Rheumatology, 2016, 12:374-375).

D) Stem cell therapy in autoimmune and musculoskeletal diseases

• We have developed adult mesenchymal stem cell lines from bone marrow and adipose tissues of mice, dogs, horses and human. These stem cells are well characterized for stem cell markers and in vivo tissue regeneration. Mouse MSCs were used for treating the experimental animal model of rheumatoid arthritis. We found that adipose tissue-derived MSCs prevent pathological bone loss, suppresses autoimmune T cell responses and ! 8! promote immune tolerance by increasing the percentages of peripheral regulatory T and B cells in mice (Garimella et al., 2015, The Journal of Immunology 195:5136-5148).
• In preliminary studies we also observed that MSCs suppresses the inflammation in clinical cases of osteoarthritis in dogs. Overall our research leads strongly suggest the potential role of IL-3 in prevention of pathological bone and cartilage loss and induction of immune tolerance. IL-3 also to stimulate the regeneration of bone and cartilage tissues from stem cells in osteoporosis and osteoarthritis and promote immune tolerance in rheumatoid arthritis,. Our novel research work has featured in several high impact international journals and patents; and highlighted twice in Nature Reviews Rheumatology Journal.

Publications

Patents

Mentorship provided to Ph.D. and M.D.S/M.V.Sc./M.Sc. students and postdoctoral fellows.

Guided: 14 PhDs and 11 MSc/MVSc/MDS students and 3 postdocs. Currently guiding 7 PhD students and mentoring 2 postdocs and 1 technical officer.

Awards/Honours/Memberships

• FAMS, Fellow, National Academy of Medical Sciences (NAMS), India.

• FNA, Fellow, Indian National Science Academy (INSA).

• FNASc, Fellow, The National Academy of Sciences, India (NASI).

• FNAVS, Fellow, National Academy of Veterinary Sciences

• Tata Innovation Fellowship, by Dept. of Biotechnology (DBT), Govt. of India.

• National Bioscience Award for Career Development by DBT, New Delhi.

• B. M. Birla Award by the B. M. Birla Science Centre, Hyderabad.

• Prof. B. K. Bachhawat International Award by Christian Medical College (CMC), Vellore, India.

• Elected Member, Guha Research Conference (GRC).

• Elected Member, Molecular Immunology Forum (MIF).

• DBT Overseas Associate-ship Award by DBT, New Delhi.

• Commonwealth Fellowship Award, England.

• Gold Medal during M.V.Sc. degree.

• ICAR Merit Scholarship during B.V.Sc.& A.H.

Honors

• Nominated by President, Govt. of India for attending South Asian Association for Regional Cooperation (SAARC) meeting at University of Karachi, Karachi, Pakistan, Oct. 10, 2003-Oct 15, 2003.

• Chancellor Nominee as an Executive Council (Senate) Member, Maharashtra Animal and Fisheries Sciences University, Nagpur, 2009-2014.

Memberships

Member of international and national professional bodies

• Member, The American Association of Immunologist, USA

• Member, The American Society for Bone and Mineral Research, USA.

• Life Member, Indian Society of Cell Biology, India.

• Life Member, Society of Inflammation Research.

• Member, International Chinese Hard Tissue Society, China.

• Executive Committee Member, Indian Society of Cell Biology 2007- 2009.

• Life member, Laboratory Animal Association of India.

• Life Member, Laboratory Animal Scientists Association

Invited talk delivered/Chaired Scientific Sessions : 61

Other administrative responsibilities

• President, NCCS Staff Welfare Society.
• Scientist in-charge Central Sterilization Facility of NCCS.

Current/Past Lab Members

• Shruti M. Khapli (PhD completed)
• Latha S Mangashetti (PhD completed)
• S. D. Yogesha (PhD completed)
• Geetanjali Joshi-Tomar (PhD completed)
• Navita Gupta (PhD completed)
• Rupesh Srivastava (PhD completed)
• Amruta barhanpurkar (PhD completed)
• Hiral M Jhaveri (M.D.S. completed)
• Christie Aguiar (M.V.Sc. completed)
• Supinder Kaur (JRF, registered for PhD)
• Gayatri Manasa (JRF, registered for PhD)
• Snehal Joshi (JRF, registered for PhD)
• Vikrant Piprode (JRF, registered for PhD)
• Kanupriya Singh (JRF, registered for PhD)
• Satish T Pote, (Lab Technician)