Earlier in the year this study linked a decline in mitochondrial function to bone loss and osteoporosis. In this just released report researchers observed that Sirtuin1 (Sirt1) improves osteogenesis (= bone formation). Sirt1 is a deacetylase dependent on the availability of nicotinamide adenine dinucleotide (NAD+) and therefore also linked to mitochondrial health. Studies have shown that as we age NAD+ levels decline hand in hand with impaired mitochondrial function.
Osteoporosis causes bones to become weak and brittle so that a fall or even mild stresses such as bending over can cause a bone fracture. Osteoporosis-related fractures most commonly occur in the hip, wrist or spine. Bone is in fact living tissue that is constantly being broken down and replaced. Osteoporosis occurs when the creation of new bone doesn’t keep up with the removal of old bone. Strengthening of osteogenesis (= bone formation) may therefore be an effective way to relieve osteoporosis.
Many studies show that Sirt1, a class III deacetylase, plays a critical role in regulating cellular metabolism and several biological functions, including lifespan, stress, and inflammation. Its presence has been confirmed in both the cytosol and the nucleus, where it deacetylates a host of regulatory proteins and transcription factors, such as p53, PGC-1α, p300, FOXO1, nuclear factor-κB (NF-κB), and others. Its action on the p53 protein has been shown to promote osteoblast differentiation (= “creation” of cells that synthesize bone) of mesenchymal stem cells (MSCs) in mice. Other earlier studies have also suggested that Sirt1 dysregulation might be involved in the development of osteoporosis.
The underlying mechanism of action of Sirt1 in osteogenesis and osteoporosis remains however not fully understood. Here the researchers hypothesized that the mechanism may depend on the inhibition of peroxisome proliferative-activated receptor γ (PPARγ) expression by Sirt1, because PPARγ has been shown to be a major inhibitor of osteoblastogenesis. PPARs are nuclear receptors which induce peroxisomal proliferation. Three types of PPARs have been identified to date: PPARα, PPARβ/δ and PPARγ. Among them, PPARγ participates in glucose, amino acid, and lipid metabolism. The researchers noted that activation of PPARγ by Rosiglitazone stimulates the differentiation of adipocytes (=fat cells) over osteoblasts (=cells that synthesize bone) from mouse bone marrow MSCs, resulting in a decrease in bone mineral density. In addition, large aggregation of adipocytes in the bone marrow of patients with osteoporosis has been found, possibly due to the activation of PPARγ. All together this suggests that PPARγ might impact bone metabolism by stimulating the differentiation of MSCs into adipocytes instead of the needed osteoblasts that synthesize bone.
To test their hypotheses the researchers setup an experiment using mouse pre-osteoblastic MC3T3-E1 cells under osteogenic differentiation and investigated the interaction between Sirt1 and PPARγ. They used plasmid transfection as method to overexpress Sirt1. The results showed that high expression of Sirt1 was associated with increased osteogenic differentiation. Sirt1 overexpression also directly and negatively regulated the expression of PPARγ and its downstream molecules. The use of the earlier mentioned PPARγ agonist Rosiglitazone, reversed the effects of Sirt1 on osteogenic differentiation. These results suggest a novel mechanism for Sirt1 in osteogenic differentiation through downregulation of PPARγ activity.
Alltogether this points to a Sirt1–PPARγ pathway that may represent a potential target for enhancement of osteogenesis as part of a treatment of osteoporosis. It also adds to the growing body of evidence that maintaining mitochondrial functioning as we age may help to avoid or delay these aging related diseases. Substances that likely improve mitochondrial functioning, and SIRT1 activity, are for example nicotinamide riboside that increases the NAD+ pool and flavonoids like quercetin through protection of the NAD+ pool from depletion.