One in three female and one in eight males are affected from osteoporosis over the age of fifty, making India as one of the highest affected regions in the world. Osteoporosis increase the susceptibility to fractures. Besides, accidental fracture rates are highest in India. Our interest is focused on identification of stimulating factors which enhance bone mass and accelerate bone healing. For this, the strategy is to design compounds with dual bone anabolic and anti-catabolic effects. Taking leads from natural products, various compounds were synthesized by systematic variations of functional groups for the treatment of bone and related disorders. Among them, CDRI compounds CDRI-S007-1500 and CDRI-S008-399 remarkably promoted osteoblast differentiation and mineralization.
CDRI-S008-399: Design, synthesis and extensive biological studies with CDRI-S008-399 established its dual anabolic and anti-catabolic effects in ovariectomized osteopenic Sprague Dawley rats. CDRI-S008-399 enhanced new bone formation and decreased the level of CTX, a collagen breakdown product and bone resorption marker. The compound acted via the stimulation of ER/p38MAPK/p-Smad signaling pathway. CDRI-S008-399 promoted rapid fracture healing in mice femur osteotomy model. These studies have led to the technology transfer of osteogenic compound, S008-399, as a medicated biodegradable bone implant to Orthoregenics Pvt Ltd, Hyderabad. For this study, our CDRI team received the CSIR Technology Award for the year 2019. US patent number 8686028 (Grant date 01.04.2014).
CDRI-S007-1500: Taking lead from medicarpin, a natural pterocarpan derived from Butea monosperma, several synthetic pterocarpans were derivatized. Out of these, CDRI-S007-1500 was identified as a potent lead as it enhanced osteoblast differentiation and mineralization at a very low dose of 1pM. Its bone healing and fracture repairing property was evaluated in rodents and rabbit models. CDRI-S007-1500 stimulated fracture healing at a very low dose of 1.0 mg/kg body weight dose. The compound is found to be safe in various toxicity and safety pharmacology studies and has no off-target effects. Compound CDRI-S007-1500 is open for licensing and process is on for its IND filing. US patent number 8686028 (Grant date 01.04.2014).
Vehicle CDRI-S007-1500
Osteoimmunology
A growing understanding of the bone remodeling process suggests that inflammation significantly contributes to the pathogenesis of osteoporosis. T cells and various cytokines contribute majorly to the estrogen deficiency-induced bone loss. Among the various Th subsets, IL-17 cytokine producing Th17 has been identified as the major osteoclastogenic subset. IL-17 serum levels were elevated in autoimmune disorders like rheumatoid arthritis. However, its role in estrogen deficiency induced bone loss was not explored. Studies by our group have shown that IL-17 is an important mediator of estrogen deficiency induced bone loss. Th17 effector subset is regulated by several other cytokines. These include members of IL-12 cytokine family like IL-27, IL-23, IL-12 and IL-35. While IL-12 and IL-23 are predominantly pro-inflammatory cytokines, IL-27 and IL-35 are anti-inflammatory in nature. We have studied both the effects of IL-27 supplementation and IL-23 neutralization in ovariectomized estrogen-deficient mice on various immune and skeletal parameters. Our studies reveal that supplementation of IL-27 to ovariectomized mice had osteoprotective effects by suppressing Th17 cell differentiation. With IL-23 it was observed that functional block of IL-23 prevents ovariectomy induced bone loss by reducing TH17 differentiation. Overall our studies suggest that monoclonal antibodies against pro-inflammatory cytokines and supplementation of anti-inflammatory cytokines may be a promising approach for management of osteoporosis.
MicroRNAs in regulation of osteoblast functions
Our studies have identified several novel microRNAs which negatively regulate the process of bone formation. These include miR-542-3p, miR-467g, miR-376c, miR-409-5p and miR-1187. Overexpression of these microRNAs leads to a significant deterioration of the bone microarchitecture while silencing of these microRNAs has positive effect on bone formation. All these microRNAs target specific genes for carrying out their bone suppressive effects and might be interesting therapeutic options for management of osteoporosis.