The biologic mechanisms involved in the pathogenesis of multiple myeloma (MM)-induced osteolytic bone disease are poorly understood. Physiological interactions between the serotoninergic and skeletal systems have been implicated by clinical observations. Brainstem-derived serotonin positively regulates bone mass following binding to 5-HT2C receptors on ventromedial hypothalamic neurons. This is opposed by platelet-derived serotonin that induces bone lysis and osteoclast activation. Moreover, the serotonin transporter SLCA6A4 is universally present among the malignant B cell clones.
We examined serotonin dysregulation in two sample types from MM patients: peripheral blood and bone marrow. In the blood we measured by ELISA the ratio of serotonin in serum compared to platelets in patients with MM (n=10), MGUS (n=10) or healthy controls (n=5). We found higher levels of serotonin in platelets for the MM patients compared to the MGUS & healthy controls (p=0.017). Concomitantly there was less serotonin in the serum of MM patients compared to compared to the MGUS & healthy (p=0.002). This implies an imbalance in the compartmentalization of serotonin associated with presence of MM bone disease.
Our multiplexed protein kinase signal pathway mapping technology, reverse phase protein microarrays (RPMA), was applied to bone marrow samples for quantifying post-translational modifications (e.g. phosphorylation, cleavage, acetylation) and/or total cell signaling kinase levels.
Using reverse-phase protein microarray (RPMA) we retrospectively measured bone remodeling signal pathway perturbations in 15 bone marrow core biopsies from patients diagnosed with MM, at different clinical stages, and correlated this with the presence of MM-related bone disease (documented by scan or MRI). Bone marrow core biopsies exhibited significant elevation of cellular Serotonin, RANK, MMP-11, TNFα, TNF-R1, and Ezrin Tyr353 in MM with active bone disease (n=9) compared to patients without bone disease (n=6) (respectively p=0.031, p=0.038, p=0.0082, p=0.0221, p=0.01, p=0.028).
To further evaluate the serotonin dysregulation in bone marrow cells, we measured serotonin bound to plasma cells (CD138+) compared to CD138- cells in bone marrow aspirates (n=21). Bone marrow aspirate were collected from patients undergoing standard of care hematological work up for multiple myeloma at any stage or treatment course. Patients with symptomatic myeloma (defined as presence of at least one of CRAB symptom) had lower serotonin levels in the CD138- bone microenvironment cells compared to non-symptomatic patients (p=0.0235). Plasma cells (CD138+) exhibited larger amounts of serotonin compared CD138- bone microenvironment cells (p=0.016).
Taken together, our data show a dysregulation of serotonin in MM suggesting an altered distribution of serotonin in blood and bone marrow. This provides potential insights into diagnosis, prognosis, and/or treatment.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.