Hidden Hormone

A recent study reported uncovering a novel brain-derived hormone  called CCN3 which is responsible for increased bone mass in postpartum lactating mothers.

About the study

• Published In: The study is published in the journal Nature
• Hypothesis: An another way to strengthen bones, independent of oestrogen in the body was suspected for a long time,
  • During pregnancy the body suppresses oestrogen production in the ovaries leading to weaker bones in females, but it was observed that the mothers’ bones become stronger in this time to meet the high calcium demands of their babies and to make up for bone loss during pregnancy.

• The Study

• • Mice genetically modified to not produce a protein called oestrogen receptor alpha in the hypothalamus were used for the experiment.

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• • • The researchers isolated a specific skeletal stem cell population from wild-type mice and transplanted them into mutant mice. The result was higher bone mineralisation in the mutant female mice.
  • Factor Identification: The researchers put the mutant mice on a high-fat diet (lost bone mass) which will affect the function of KISS1 neurons to identify the factors driving such changes.
    • Of the two genes (Ccn3 and Penk) only the hormone produced by the Ccn3 gene, called CCN3  was found to be located in all the KISS1 neurons in the mutant mice.
  • As an Osteoanabolic Hormone: The researchers established the role of CCN3 as an osteoanabolic hormone (involved in making bone) by extracting skeletal stem cells from wild-type mice and cultured the cells with the CCN3 hormone recording  a 200% increase in mineralisation.

• Result

  • Bone Mineralisation: Researchers found that specific neurons, called KISS1 neurons, used the CCN3 hormone to maintain bone mineralisation during lactation.
    • KISS1 neurons: They are located in the arcuate nucleus (ARC), a critical part of the hypothalamus that regulates metabolism, reproduction, and bone health. KISS1 neurons are key to regulating bone mass in females.
  • Bone Repair: Low doses of mouse CCN3 significantly increased the bone mass of young and aged femurs and of adult wild-type mice. In two-year-old male mice with bone fractures, treatment with CCN3 accelerated bone repair 
  • A Sex-Specific Regulatory Mechanism: CCN3 had been explicitly upregulated in mutant female mice but not in wild-type mice or in mutant male mice suggesting a unique response by the mutant female mice highlighting a potential sex-specific regulatory mechanism of bone formation involving CCN3.
  • Bone Formation: CCN3 increased the frequency and potential with which skeletal stem cells matured into cells that form bone and cartilage. 
    • The hormone helped produce more cells that built bones and cartilage and made these cells better at doing their job, leading to stronger and healthier bones.
  • Maternal Bone Mass and CCN3 hormone: It was found that lactating mothers with low CCN3 and a low-calcium diet had lower bone density, negatively affecting the survival of their offspring.
    • In mice,the CCN3 is observed to be absent during early and late pregnancy, appears within seven days after birth, and drops again as lactation decreases. 

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• Significance

• • Therapeutic Agent: CCN3 identification  presents new opportunities to investigate its potential as a therapeutic agent for hereditary and chronic skeletal disorders, broadening the range of treatment choices for osteoporosis.
  •  CCN3 can be established as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.
  • Broader Understanding of Hypothalamus: The study revealed a pathway in which hypothalamic neurons sidestep conventional routes to directly release hormones into the bloodstream, providing fresh perspectives on the communication between the brain and the body.
  • Maintain Maternal bone mass: The study can now open new avenues to maintain bone mass in pregnant and lactating mothers.
  • Application: The results were replicated in male and female human skeletal stem cells as well, confirming its broad applicability.

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