Cystatin M/E ameliorates bone resorption through increasing osteoclastic cell estrogen influx

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Multiple myeloma (MM) causes osteolytic lesions due to increased osteoclast differentiation.
• Current treatments like bisphosphonates have limitations, necessitating novel agents for bone resorption inhibition and lesion repair.
• Elevated cystatin M/E (CST6) levels correlate with an absence of osteolytic lesions in MM.

Approach:

• Compared recombinant mouse CST6 (rmCst6) with zoledronic acid (ZA) in MM and ovariectomy (OVX)-induced osteoporosis mouse models.
• Utilized micro-computed tomography (μCT) and single-cell RNA sequencing to assess bone volume and cellular changes.
• Analyzed protein and mRNA arrays to evaluate cytokine expression and estrogen receptor (ERα) levels.

Key Points:

• Both rmCst6 and ZA improved bone volume and inhibited osteoclast differentiation in mouse models.
• rmCst6, unlike ZA, reduced bone marrow macrophage percentage in the MM model.
• rmCst6 normalized ERα expression in OVX mice and increased ERα and intracellular estrogen in osteoclast precursors.

Conclusions:

• CST6 mitigates bone loss in MM and OVX models by upregulating ERα and intracellular estrogen concentrations.
• This mechanism inhibits osteoclast precursor maturation, offering a novel therapeutic strategy.
• CST6 demonstrates potential as an anti-bone resorption agent with unique mechanisms compared to ZA.