Skeleton Crews
Safety Assessment
Rana Samadfam, PhD

Skeleton Crews

The cross talk between bones and the immune system are striking, complex and not always welcome.

The traditional view of bone as an assembly of inert calcified tubes solely responsible for supporting and protecting vital organs is gradually fading away, and rightfully so.

The skeleton is now recognized as an endocrine organ with an important role in the regulation of a number of metabolic processes (see Eureka blogs here, here, here and here), muscle function and strength (see Eureka blog) and even the reproductive system.

Nor do the connections end there. Evidence indicates there is important cross talk between bone and the immune system under both physiological and pathophysiological conditions. These two systems are closely related through cellular and molecular interactions and they share several cytokines, signaling pathways, and transcription factors. 1

Osteoclasts: a member of the immune system

A clear example of these shared signaling pathways is the RANK/RANKL pathway.  This pathway is essential for the differentiation and function of osteoclasts (OCs), giant, multinucleated cells responsible for bone resorption. RANKL is a cytokine that is expressed by T-cells and osteoblasts. Its receptor, RANK is expressed on osteoclast precursors, pre-osteoclasts and mature osteoclasts, and its activation results in differention and fusion of pre-osteoclasts and formation of mutinucleated mature osteoclasts.

This pathway is also essential for the activation and survival of mature osteoclasts. Once activated, osteoclasts recognize specific proteins on the bone matrix and after binding to these proteins they start digesting it. This same pathway is also essential for lymphocyte differentiation. In fact, RANKL, also known as TNF-related activation induced cytokine (TRANCE), and its receptor RANK were first identified in immune cells (expressed by T cells and dendritic cells (DCs), respectively). Moreover, their interaction increases the ability of DCs—which patrol the body for pathogens and deliver them to lymph nodes (the hub of the immune system) –to stimulate naive T cell proliferation and DC survival. Therefore it should not be surprising that disturbances in this pathway affect both skeletal and immune systems.

Recent findings also show striking similarity between DCs and osteoclasts. Both cell types express major histocompatibility complex classes I and II, and various proteins that in different ways are integral to immune regulation and function.2 OCs present allogeneic antigens and activate both CD4 and CD8 T cells. Furthermore, OCs can function as antigen-presenting cells and activate both CD4 and CD8 T cells. 2 Because of these important similarities, osteoclasts can be classified as a member of the immune system, or at least a close cousin3!

Sometimes, the interactions are problematic. Bone loss induced by immunosuppressants, including glucocorticoids, drugs acting on immunophilins (Sirolimus) and cytostatics, have been reported.4 Consistent with published data, we recently reported at the Society of Toxicology meeting in March that the treatment of aged rats with glucocorticoids is associated with bone loss and attenuated growth. These effects were consistent with decreases in bone formation. In general, the negative effects on bone size and bone mass persisted after drug withdrawal.

Furthermore, osteoporosis, a well characterized bone disease, is now considered an immune-mediated disease in which abnormal T-cells can activate the RANKL/RANK pathway and consequently induce bone loss. The role of T-cells and the RANKL/RANK pathway in bone destruction during the course of inflammatory diseases and other diseases such as multiple myeloma, has been well documented. Even some hormonal imbalances have been shown to modulate bone density by regulating the immune system.

These findings paint a complicated picture for the cross talk between the immune system and bone with the potential for multiple interactions and a complex regulatory system to maintain optimal function. The complex interactions underscore the need to bone up and include skeletal evaluations in toxicology studies as part of a multidisciplinary approach to drug testing.


  1. Clin Devl Immunol 2013 doi: 10.1155/2013/720504
  2. Blood 116 (2) 210 2010
  3. Medicographia 32, (4) 341 2010
  4. J Orthop Res 27(9) 1157–1161 2009