Cystinosis metabolic bone disease: inflammatory profile in human peripheral blood mononuclear cells and derived osteoclasts.

Unlabelled: Cystinosis metabolic bone disease (CMBD) is an emerging concept in infantile nephropathic cystinosis, patients presenting with bone pains, fractures, and deformations during teenage or early adulthood. The underlying mechanisms remain unclear. Our aim was to explore the pro-inflammatory profile of osteoclastic lineage in cystinotic patients. We obtained blood samples from 14 cystinotic patients and 10 pediatric healthy controls. Peripheral blood mononuclear cells (PBMCs) were isolated and used to explore by RT-qPCR the transcript expression of 8 inflammatory markers (Il-6, Il-8, Il-1β, CXCL1, CCL2/MCP-1, CXCR3, Il-1 Receptor, Il-6 Receptor). In addition, when possible, PBMCs were differentiated into osteoclasts for further experiments. The expression of Il-6, IL-8, CXCR3, and CCL2/MCP-1 was significantly increased in PBMCs from cystinotic patients. We also explored the expression of Il-1 Receptor and Il-6 Receptor, two major pro-osteoclastic signal inducers, in osteoclasts differentiated from PBMCs from controls (N = 3) and patients (N = 4). The expression of IL-1 Receptor (but not IL-6 receptor) was increased in osteoclasts obtained from cystinotic patients.

Conclusion: There is an inflammatory profile in PBMCs and osteoclastic lineage in cells obtained from cystinotic patients. CXCR3 and MCP-1 stimulate migration and activation of macrophages, that may explain the previously reported local increased osteoclastogenesis. The osteoclastic overexpression of IL-1 Receptor is a relevant observation in the field since blocking Il-1β signaling has recently been proposed as a novel therapeutic approach to improve muscular wasting in this orphan disease.

What Is Known: • Cystinosis metabolic bone disease (CMBD), an emerging concept with unclear underlying mechanisms, induces bone pains, fractures and deformations in patients with cystinosis. • Blocking Il-1β signaling may be a novel therapeutic approach to improve muscular wasting in cystinosis.

What Is New: • There is an inflammatory profile in PBMCs and osteoclastic lineage in cells obtained from cystinotic patients, with an over-expression of IL-1 Receptor in osteoclasts. • We provide another experimental rationale to propose targeted anti-inflammatory therapies in cystinotic patients with severe bone disease.