1st Day-3rd Talk: “Bones and Regenerative Medicine” by Michael Rosenblatt, M.D.

Dr. Rosenblatt is a professor of Physiology and Medicine & the Dean of Tufts University School of Medicine. His presentation discussed the use of growth factors to promote bone production. There are stem cells present in bone marrow that can be used to regenerate bone; however, these stem cells contribute to the normal aging process. There may be a bone “aging program” built into these stem cells that is controlled by a general set of genes for aging, and the manipulation of the aging genes by pharmacological approaches may offer a “stem cell” opportunity to prevent and/or reverse bone disease (i.e. osteoporosis) without the use of stem cells.

Humans reach their peak bone mass at 25 years of age. Women will lose 50% of their skeleton over their lifespan after the age of 25. Men have a higher peak mass because they do not undergo menopause or testosterone withdrawal, but they will also start losing bone mass every year after the age of 25. Osteoporosis is a very prevalent degenerative bone disease in our population. Approximately 44 million people are affected. 10 million currently have osteoporosis and 34 million are affected by a condition of low bone mass known as osteopenia. Half of women and 20% of men over the age of 50 will suffer from fractures. The mortality rate is 10-20% in the first year after a hip fracture, and the costs associated with these conditions is approximately 18 billion annually.

Normal remodeling of bone tissue consists of osteoclast recruitment and activation, reabsorption and osteoblast recruitment, and osteoblastic bone formation. Healthy bone balances reabsorption with formation. A healthy human will turn over bone at a rate of 5-6% per year.

The mechanistic approaches to osteoporosis treatment are to block bone reabsportion and increase bone formation (an anabolic process). Most of the current therapies (i.e. bisphosphonates, SERMs, HRT, parathyroid hormone (PTH)- anabolic) block bone resporption.

How do the anabolic treatments differ from the others? The refill of bone mass is greater when using anabolic agents. Dr. Rosenblatt presented a study that showed mice treated with PTH and FGF. FGF was shown to increase bone mineral density within 5 days of treatment. After 3 weeks, there was a 25% increase in bone density observed in the mice that were treated with FGF.

An interesting report in the New York Times in July 2005 showed that holes in osteoporotic bones were filled with fat. Stem cells contain 1 billion years of “engineering” and are at the balancing point between fat and bone tissue because mesenchymal cells (marrow stem cells) can differentiate into adipocytes or osteoblasts. In other words, as Dr, Rosenblatt so eloquently phrased it, “fat gain is bone loss”.

The Wnt signaling pathway is the key stimulator of osteogenesis. People with mutations in the gene lrp5 increase bone marrow density. PPARγ is the master gene in adipocytes. This gene codes for a transcription factor; it is a member of the nuclear hormone receptor super-family. This transcription factor binds to PPAR responsive elements in the promoter region of target genes. PPARγ-deficient embryonic stem cells from homozygous recessive mice (PPARγ -/-) spontaneously differentiate into osteoblasts. There was also increased bone mass and decreased marrow adipocytes observed in PPARγ-deficient mice.

How is aging related to bone loss? Men and women both lose bone with age, but the question is, are there genes associated with aging which intersect with bone-regulating genes? If yes, can these genes (and the stem cells which express them) be manipulated to prevent and/or reverse aging? SIRT-1 is an NAD-dependent histone deacetylase that plays a key role in chromatin remodeling associated with gene silencing. It has been found that calorie restriction extends life span. Thus, Dr. Rosenblatt’s research hypothesis is that SIRT-1 plays a role in the reciprocal relationship between osteoblast and adipocyte differentiation from their common progenitor stem cell in the bone marrow, and this may possibly occur through action of as a PPARγ repressor. His research has shown that the over-expression of SIRT-1 increases osteoblastogenesis. Down-regulation of SIRT-1 inhibits osteoblastogenesis and increases adipogenesis.

Dr. Rosenblatt discussed the future of research in this area may be a number of agents (growth factors, etc.) that can be used instead of stem cells to treat osteoporosis.