Osteoporosis and IFT80

[corybroo]

Intervening to stop bone loss

the protein IFT80 [is] a key player in keeping populations of osteoclasts in check.

IFT, or intraflagellar proteins, play a role in T cell protein transport. … IFTs play critical roles in regulating osteoblasts and chondrocytes, cells that maintain cartilage, from mesenchymal stem cells, which make and maintain bone, cartilage, and other tissue types.

Yang's group developed a knockout mouse line that lacked the protein in precursors of osteoclasts. Notably, they found these animals had significantly lower bone volume compared to normal mice, and their osteoclasts nearly doubled in number.

The researchers found that IFT80 prevents osteoclast precursors from giving rise to the bone resorbing cells and inhibits osteoclast maturation.

Yang's team found that IFT80 prevents the breakdown of Cbl-b, and Cbl-b normally degrades another protein called TRAF6. TRAF6 normally promotes osteoclast production, so by degrading TRAF6, IFT80 inhibits osteoclast differentiation.

To test the idea of IFT80 being a potential target for intervention in bone loss disorders, the researchers overexpressed IFT80 in a mouse model that normally experiences overactive osteoclasts-caused bone loss. Doing so effectively tamped down RANK/RANKL activation, lowered osteoclast production, and increased bone volume in the mice.

[Saul]

Hi Corybroo!

My suspicion is, that, like lowering Rank/Rankl, what you are accomplishing is: slowing down the rate of bone recycling.  This is similar to what drugs like fosimax accomplish.

This usually works well, if the patient is a postmenopausable female -- the reason is, that postmenopausible females are, in general, rapid bone remodellers -- and, normally, bone remodelling loses more bone mass than it creates.  Slowing dwon the remodelling rate -- usually by killing, or otherwise inhibiting osteoclasts, accomplishes that.

However, this procedure almost never works for older males.  Adult males with osteoporosis, especially the older ones, almost always are very slow remodellers, partly they are much lower in serum estrogen, which brings about rapid remodelling.  So drugs like Fosimax, or Prolia (which effects the Rank/Rankl cycle) -- or, probably IFT80, are useful for them -- but these same treatments usually have the opposite effect on adult males.

  --  Saul

 

[corybroo]

A small, short study of young, healthy people.

Small daily portion of Jarlsberg cheese may help to stave off bone thinning

A small (57 g) daily portion of Jarlsberg cheese may help to stave off bone thinning (osteopenia/osteoporosis) without boosting harmful low density cholesterol

the researchers studied 66 healthy women (average age 33; average BMI of 24) who were randomly allocated to adding either a daily 57 g portion of Jarlsberg (41) or 50 g of Camembert cheese (25) to their diet for 6 weeks.

Jarlsberg and Camembert have similar fat and protein contents, but unlike Camembert, Jarlsberg is rich in vitamin K2, also known as menaquinone (MK)

[While] short-chained MK-4 is found in animal products such as liver, Jarlsberg is particularly rich in both [long-chained]  MK-9 and MK-9(4H).

Blood fats increased slightly in both groups after 6 weeks. But levels of total cholesterol and LDL (harmful) cholesterol fell significantly in the Camembert group after they switched to Jarlsberg.

Calcium and magnesium fell significantly in the Jarlsberg group but remained unchanged in the Camembert group. After switching cheese, calcium levels dropped in this group too, possibly reflecting increased uptake of these key minerals in bone formation, say the researchers.

The bacteria (Proprionebacterium freudenreichii) in Jarlsberg that produces MK-9-(4H) also produces a substance called DHNA, which, experimental studies suggest, might combat bone thinning and increase bone tissue formation, and possibly explain the increase in osteocalcin, they add

[Sibiriak]

12 hours ago, corybroo said:

A small, short study of young, healthy people.   Small daily portion of Jarlsberg cheese may help to stave off bone thinning

Funding: Norwegian Research Council

"We promote competitiveness and growth in Norwegian trade and industry by providing financial support and advice for research and innovation projects "

Jarlsberg is produced in Norway, as well as in Ireland and the US state of Ohio, licensed from Norwegian dairy producers.  (Wiki)

Edited August 3, 2022 by Sibiriak

[mccoy]

I don't know about Menaquinone MK-4 and the alleged properties of Jarlsberg cheese, but I'd love to taste it, never had the opportunity to. I know Camembert, but I don't like it, too fatty.

[mccoy]

OK, looked up at Jarlsberg's macros, 31% fats, I'd just like a sample once and that's all.

There are a few low fat cheese products which are even more palatable than the fatty ones (low fat feta being one of my favourites).

[corybroo]

42 minutes ago, mccoy said:

OK, looked up at Jarlsberg's macros, 31% fats, I'd just like a sample once and that's all.

There are a few low fat cheese products which are even more palatable than the fatty ones (low fat feta being one of my favourites).

Thanks, McCoy.  I see that my local Publix offers a Jarlsberg Lite Swiss cheese.  I don't know if that has the vitamin K2 long chains which would be the main reason I would add it to my diet.  Interestingly, the serving size is 28g which is just under half the amount used in the study.  Two such servings would add 140 calories (20% of daily sat fat, and 40% of calcium).  https://www.publix.com/pd/jarlsberg-lite-cheese-reduced-fat-swiss/RIO-PCI-523405

Sibiriak's comments are worth noting - Funding guides findings as Marion Nestle has frequently reported.  If I were worried about osteoporsis right now, I'd take the gamble and work the two servings into my diet today.  If not, then I'd weigh the sat fat concerns more heavily and wait for successful replication of the study.  YMMV  

[Sibiriak]

Jarlsberg cheese study shredded by experts

Quote

Prof Jonathan Reeve, Honorary Senior Research Fellow, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, said:

“In my opinion this paper stretches credulity.  A bone anabolic response implies that more bone tissue has been formed than in the control group.  This is not proved to be the case; a biochemical marker that may or may not co-correlate with bone formation has been shown to increase with Jarlsberg consumption.  The recommendation to consume K2 (one of the forms of vitamin K) to prevent osteoporosis was unique to Japan so far as I know and dates from 11 years ago, not being replicated outside the Far East.

“There is a potential confounder that I don’t think has been adequately discussed.  Jarlsberg contains very little lactose whereas I know to my personal annoyance that most other good cheeses contain lots.  Many European adults of a certain age (and especially Chinese and Japanese) suffer from mild to severe degrees of alactasia (acquired deficiency of the intestinal enzyme lactase that enables the disaccharide lactose to be split into glucose and galactose; varying proportions of European adults have alactasia ranging from about 0% in the Dutch to over 5% in some other populations, it’s higher in the far East) which might have confounded the interpretation of mechanisms underlying the results found in this study, since too much lactose-containing cheese in those affected causes diarrhoea – bad for calcium absorption (apart from jarlsberg I have to eat cheddar that has had the lactose converted to glucose and galactose which I can absorb).

“Biochemical markers correlate quite poorly in general with the results of serial bone densitometry, though this is not always true.  The authors might have served science better to have done a 1 year bone densitometry study.”

 

Prof Tom Sanders, Professor emeritus of Nutrition and Dietetics, King’s College London, said:

“This study conducted in younger women (mean age 33) compared the effects of eating Jarlsberg cheese with that of consuming camembert cheese on the amount of osteocalcin in the carboxylated form which plays a role in bone resorption and helping maintain bone mineral mass.  Osteocalcin is a vitamin K dependent glycoprotein that needs to be converted to a carboxylated form, so it can bind calcium, by the action of vitamin K.  Some hard cheeses such as Jarlsberg contain substantial amounts of forms of vitamin K, called menaquinones, that are formed by bacterial during prolonged fermentation.  Soft cheeses such as camembert contain very little because they are not fermented for so long.

“The aim of this study was to compare a cheese high in menaquinones with one low in menaquinones.  However, there were major flaws in the dietary design of this study.  Firstly, they fed 57 g Jarlsberg cheese per day compared with variable amounts of camembert, 30-60 g per day. 

Secondly, they failed to take into account that camembert contains much more water than Jarlsberg so the protein and fat content differed substantially between treatment groups: the Jarlsberg treatment group provided 16g each of fat and protein per day compared with 6-12 g each in the camembert group.

“This is an RCT but obviously not blinded and the outcomes are surrogate risk markers for osteoporosis/osteopenia.  In order to demonstrate a reduction in risk requires a hard end point such as a reduction in bone density or increased incidence of fractures.

“The study did find an effect on the main outcome which showed an increase in the level carboxylates osteocalcin and was consistent with the higher levels of menaquinone metabolites (forms of vitamin K derived metabolites of bacterial origin supplied by Jarlsberg cheese).  It also found a change in a related protein PINP.  The report also suggests a more favourable changes in blood lipids, particularly LDL cholesterol for the Jarlsberg cheese, but this is not justified as the statistical test between treatment was not significant.  Some minor changes in glycosylated haemoglobin levels were found but this could be a play of chance and anyway are of no clinical significance as the participants did not have diabetes.

“The press release describes 57 g as a small daily portion of Jarlsberg cheese – that is about the size of two matchboxes – and claims this may stave off bone thinning.  A small portion is 15 g and average daily intake are about 18 g of cheese in the UK and even in France which has the highest per capita intake of cheese in Europe it only 45 g/d.  The reported effects are unlikely to be specific to Jarlsberg cheese and may be similar in other hard long fermented cheeses.  Finally, these changes in osteocalcin and PINP may not in the long-term translate into a reduced rate of bone thinning in women of this age.  Especially as trials of menaquinone supplements over a several years have shown no effect in reducing the rate of bone thinning in younger women.”

 

Dr Duane Mellor, Registered Dietitian and Senior Teaching Fellow, Aston Medical School, Aston University, said:

“This is a small study which was part funded by TINE SA, the manufacturers of Jarlsberg which a trademarked cheese.  It suggests that specific markers in the blood which are strongly linked to bone health are increased with daily consumption of this type of cheese in healthy premenopausal women without bone disease, however it does not provide any evidence of actual change in bone density or strength as these would take a lot longer than 6 weeks to show.

“There are concerns about the statistical approach which compared the changes seen between groups, which could not take into account the dual effects of the intervention and the duration of the study – this could mean that the significant changes reported may just be a statistical error.  This can happen in part, as it will miss differences between the groups at the start of the study.  In this case the camembert group levels of osteocalcin and vitamin K2 dropped a bit as the Jarlsberg group increased – this effect is sometimes called regression to the mean.  The researchers should have used a repeated measures approach to do this analysis so the effect of both the time participants were in the study and the intervention could be assessed properly, rather than the tests they did.

“The link to changes in vitamin K are interesting, as the Jarlsberg contained this nutrient and the control camembert did not, and this is often an overlooked vitamin which has a key role in calcium metabolism and therefore bone health.  However, there are various other sources of this vitamin in our diet including dark green vegetables including kale, as well as it being made in bacteria living in our colon (which thrive on a diet rich in fibre and a variety of plants), as the researchers only asked the participants to stick to their usual diet (which naturally varies) and did not try to control it – this could mean their intake of vitamin K could have varied both at baseline and through the study, so the measured levels of vitamin K could have been affected by other foods eaten that contained vitamin K (alongside how much was made by bacteria in the participant’s colon), rather than just being increased through eating cheese.”

 

Dr Simon Steenson, Nutrition Scientist, British Nutrition Foundation, said:

“Osteoporosis is a serious condition in which the structure of bones becomes weaker with age, increasing the risk of bones breaking.  It is estimated that more than 2 million women in England and Wales have osteoporosis, and it is the cause of around 180,000 fractures a year.  Vitamin K is a term for a family of structurally similar, fat-soluble compounds that play an important role in bone health as a cofactor for the production of proteins needed for bone formation.  This includes osteocalcin, a protein which is unique to bone and is used as a measure of vitamin K status.  Vitamin K occurs naturally as phylloquinone (vitamin K1), the predominant form found in foods (e.g. leafy green vegetables and Brassica plants such as broccoli), but is also found in animal products including meat, eggs and cheese as menaquinones (vitamin K2), which are produced by bacterial fermentation in foods and via anaerobic bacteria of the colon microbiota.  Vitamin K intake is negatively associated with risk of bone fracture, although trials of vitamin K supplements have not shown a consistent beneficial effect on bone health.

“This new study focussed on changes in markers of bone metabolism in response to consuming a particular type of cheese called Jarlsberg, produced using the bacteria Propionibacterium freudenreichii.  Jarlsberg cheese contains various forms of vitamin K, as well as 1,4-hihydroxy-naphthoic (DHNA), a metabolite secreted by Propionibacterium freudenreichii, which has been linked to lower bone resorption (bone loss).  The authors recruited 66 healthy, premenopausal Norwegian women to consume either 57 g/day Jarlsberg (J-group) or 50 g/day Camembert (C-group), which contained no vitamin K, for a 6-week period.  After 6 weeks, the C-group was switched to Jarlsberg for a further 6 weeks.  Various markers of bone metabolism were measured in blood samples to determine the effect of each cheese type on the balance between bone formation and resorption (loss).  The authors reported a significant increase in type 1 N-terminal propeptide (P1NP), total osteocalcin (tOC), carboxylated osteocalcin (cOC), and the osteocalcin ratio (ratio between cOC and uncarboxylated osteocalcin) in the J-group after 6 weeks, indicating increased bone formation.  All variables except P1NP decreased in the C-group but subsequently increased after switching to consuming Jarlsberg cheese.  The authors suggested that their findings indicate Jarlsberg cheese might have a specific beneficial effect on bone metabolism because of its content of vitamin K2 and DHNA in comparison to cheeses without these.  Clinical guidelines for the prevention and treatment of fragility fractures already include advice to ensure an adequate dietary intake of vitamin K.

“Although these are interesting and novel findings, there are a number of limitations to consider.  The diets of participants were not controlled during the intervention, and other dietary factors with a bearing on vitamin K status and bone turnover may have had an effect on results, such as consumption of vegetables containing vitamin K (e.g. broccoli, green beans, leafy greens) and other foods providing vitamin D (e.g. oily fish) or calcium, such as other dairy foods.  The authors did not gather information on the background diet of participants (e.g. using food frequency questionnaires or food diaries), and so the potential influence of these other dietary factors could not be discounted.  Notably, vitamin D deficiency was reported for nine out of the 66 subjects at baseline (six in the J-group and three in the C-group) and these individuals were given supplements to raise their vitamin D status.  Given the essential role of vitamin D in bone mineralisation, this may have affected the measures of bone turnover.

“The authors chose the amount of Jarlsberg cheese given in this study (57 g/day) as that which gives an optimal increase in osteocalcin (one of the most abundant proteins found in bone), although this was based on a single previous human trial of only 20 healthy volunteers.  Also, one of the supposed unique features of Jarlsberg cheese offered as a potential explanation for the increase in bone formation markers was its content of DHNA.  However, beneficial effects of DHNA on bone mineral density have only so far been demonstrated in mice, and so it’s unclear if a similar effect occurs in humans. 

Another point to consider is that the authors chose to contrast the effects of Jarlsberg cheese with a particular type of Camembert that did not contain vitamin K.  However, Camembert and other types of cheese (e.g. cheddar and Stilton) have been reported elsewhere to contain vitamin K, including the long-chain menaquinone forms of Vitamin K2.  Therefore, the effect of Jarlsberg may not be specific to this type of cheese alone.

“Overall, while this new study highlights an interesting avenue for potential future research, the results do not provide strong evidence of a specific beneficial effect of Jarlsberg cheese on bone health.  The authors did not directly measure bone mineral content or density, and so it’s not possible to comment on whether the favourable effect on turnover markers would translate into a genuine benefit to bone strength over time.  Although cheese can form part of a healthy, balanced diet, some types can be high in saturated fat and/or salt, and so recommending Jarlsberg cheese as a beneficial food for bone health would need to be balanced against existing dietary recommendations.

“Although vitamin K does have an established role in bone health, in terms of osteoporosis prevention it is important to remember other existing dietary and lifestyle advice.  That includes ensuring an adequate intake of calcium (700 mg/day for women; 1,250 mg/day during breastfeeding) and maintaining a sufficient vitamin D status through diet, sunlight exposure (during summer) and/or supplementation with 10 micrograms of vitamin D per day (during autumn/winter), alongside having an active lifestyle including weight-bearing exercise, which can all help to maintain bone strength.”

 

 

Edited August 4, 2022 by Sibiriak

[Todd Allen]

8 hours ago, Sibiriak said:

Jarlsberg cheese study shredded by experts

I am in shock.  I thought the Camembert control made this unshreddable.

[mccoy]

WE discussed Menaquinones in another thread, with lists of cheese and K2 content, I've been very interested on this issue, then lost the interest. Also, K2 did not succeed in eliminating nagging rib pains after I started again weightlifing, as I had hoped. I'll post the original thread.

Edited August 5, 2022 by mccoy

[mccoy]