Osteogenic inhibition in multiple myeloma
Hussain Habibi1, Saeid Abroun, Abbas Hajifathali
11. Department of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Objective:
Multiple myeloma (MM) is a plasma cell malignancy where plasma cells are increased in the bone marrow (BM) and usually do not enter peripheral blood, but produce harmful factors creating problems in these patients (e.g. malignant plasma cells over activate osteoclasts and inhibit osteoblasts with factors like RANKL and DKK). These factors are a main cause of bone lesion in MM patients. Recently SOST gene which responsible to encodes the sclerostin protein was identify. This protein specifically inhibits Wnt signaling in osteoblasts (inhibition of osteoblast differentiation and proliferation) and decrease bone formation and can also cause bone lesion in MM patients.
Materials And Methods:
In this experimental study, human myeloma cell lines (U266 b1) were purchased from Pasteur Institute of Iran. Samples consisted of BM aspirates from the iliac crest of MM patients. BM with more than 70% plasma cell were selected for our study (6 patients) and one healthy donor. RNA extraction was done with Qiagen kit. was undertaken on mRNA of samples and cell lines. Also we purchased unrestricted somatic stem cells from Bonyakhte Company to evaluate the effect of soluble factors from myeloma cell lines on osteogenic differentiation medium.
Results:
Our results showed that SOST is expressed significantly in primary myeloma cells derived from MM patients and myeloma cell lines. In other words, patients with more bone problems, express SOST in their plasma cells at a higher level. In addition, myeloma cells inhibit osteoblast differentiation in progenitor cells from umbilical cord blood stem cell (UCSC) in osteogenic inducing medium.
Conclusion:
There are many osteoblast maturation inhibitory factors such as DKK, Sfrp and Sclerostin that inhibit maturation of osteoblast in bone. Among osteoblast inhibitory agents (DKK, Sfrp, Sclerostin) sclerostin has the highest specificity and therefore will have less side effect versus non-specific inhibitory agents. Our results also show that based on SOST expression in MM, there is a potential to inhibit sclerostin with antibody or alternative methods and prevent bone lesion in MM patients with the least side effect.
Insights
Multiple myeloma patients exhibit elevated SOST gene expression, correlating with bone lesions. Targeting sclerostin may prevent bone damage with minimal side effects.
Area of Science:
- Oncology
- Bone Biology
- Molecular Biology
Background:
- Multiple myeloma (MM) is a plasma cell malignancy characterized by increased bone marrow plasma cells.
- MM-associated bone lesions stem from factors like RANKL and DKK, which disrupt bone remodeling by activating osteoclasts and inhibiting osteoblasts.
- Sclerostin, encoded by the SOST gene, is a key inhibitor of Wnt signaling in osteoblasts, further contributing to reduced bone formation and lesions in MM.
Purpose of the Study:
- To investigate the expression of the SOST gene in multiple myeloma cells.
- To evaluate the impact of myeloma cells on osteoblast differentiation.
- To explore sclerostin as a potential therapeutic target for MM-related bone disease.
Main Methods:
- Analysis of SOST gene expression in primary myeloma cells from patients and human myeloma cell lines (U266 b1).
- Collection of bone marrow aspirates from MM patients (n=6) and healthy donors.
- Assessment of myeloma cell-induced inhibition of osteogenic differentiation in umbilical cord blood stem cells.
Main Results:
- Significant SOST gene expression was detected in primary myeloma cells and cell lines.
- Higher SOST expression levels correlated with the severity of bone problems in MM patients.
- Myeloma cells demonstrated an ability to inhibit osteoblast differentiation in progenitor cells.
Conclusions:
- Sclerostin, alongside other factors like DKK and Sfrp, inhibits osteoblast maturation.
- Sclerostin exhibits higher specificity compared to other inhibitory agents, suggesting a favorable side effect profile.
- Targeting sclerostin via antibodies or other methods presents a promising strategy to prevent bone lesions in MM patients with minimal adverse effects.
