Enumeration of osteoclasts derived from monocyte subsets and its association with chronic kidney disease

Monocytes play an essential role in regulation of homeostasis. They are involved in activities like phagocytic, antigen presentation and cytokine production. Three major monocyte subsets – Classical, Non-classical and Intermediate, are identified in human peripheral blood based on surface expression of CD14 and CD16. These monocyte subsets have an ability to differentiate into osteoclasts (OC). Once differentiated, OCs are involved in bone metabolism by resorption. Though various factors are known to involve in mineral and bone dysfunction, OCs form a major contributor in bone resorption. Factors like macrophage colony stimulation factor (MCSF) and Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL) are known to activate monocyte and differentiate into OCs. Increased activation of monocyte is directly associated with increased osteoclastogenesis and higher resorption rate of bone. Contribution of each monocyte subsets to OCs is not investigated yet. In addition, contribution of other soluble serum factors such as inflammatory cytokines and chemokines in osteoclastogenesis also remains elusive.

OCs plays an important role in loss of bone mass during kidney disease. Disturbances in mineral metabolism and bone disease are common, cause considerable morbidity, and decrease quality of life in patients with chronic kidney disease (CKD). Renal osteodystrophy (ROD) is a component of the broad spectrum of mineral and bone disorders of CKD (CKD-MBD). Assessment of bone health is required for adjustment of therapy for abnormal mineral metabolism, to evaluate fracture risk, and for deciding if osteoporosis treatment is required. Though expensive radiological methods exist to determine the bone density, the metabolic status of bone metabolism is not explored to determine the rate of bone loss. To assess this metabolic state of bone, several markers are to be examined in blood during the disease progression. Hence, relationship between these soluble factors and OC frequency may allow us to design strategies to tackle increased osteoclastogenesis during disease progression.

The current proposal is to delineate the contribution of monocyte subsets in osteoclastogenesis during kidney disease. Further, to determine the relationship between frequencies of OCs, inflammatory status and associated soluble factors in kidney disease is of current interest. Determining the association of these factors with CKD will help us to design additional functional experiments to understand the molecular mechanism of this co-morbidity in CKD. These data may be promising in identifying right target(s) to reduce OC development during CKD, therefore preventing bone resorption and loss of bone density. In this study, we aim to determine the expression level of above factors and additional bone turnover markers in peripheral blood and monocytes in Indian CKD patients. This may reveal any significant association of monocyte subsets and soluble factors in osteoclastogenesis during CKD progression. Our future aim would be exploiting function of these factors and monocyte subset to identify their essential role in OC and developing drug targets against osteoclastogenesis.