The human knee is a triumph of design. The joint, which evolved fairly rapidly from our common ancestor with the chimpanzee to accommodate our bipedalism, likely contributed to our success as a species. However, as modern medicine extends the human lifespan, our species have learned pain in the form of osteoarthritis that can accompany the locomotion of this biomechanical masterpiece.
In a new study of the genetic features that help make this sophisticated joint possible, an international team of researchers found that the regulatory switches involved in the development of the knee also play a role in osteoarthritis, a partially heritable disease that afflicts at least 250 million people worldwide. The findings are published in the journal Cell.
"From an evolutionary standpoint, the primate knee went from something that accommodated the forces of walking on four legs to placing all the weight on two legs," the senor author said. "Going from a quadruped to a biped changes the force distribution. All our weight is being transmitted through our hips and our knees down to our ankles. The cells in the joint and the shape of the joint had to change to accommodate those new forces."
With such a specific task - and limited by its origins in the older primate knee - the optimized bipedal knee developed what is known as a constrained morphology, that is, it did not allow much variation. "As you can imagine, when you're designing a part for an airplane, you don't want to stray too much," the author said.
To understand how this complex mechanism came to be, researchers looked for evidence of accelerated natural selection: the series of mutations that aided us in walking upright.
What they found reflects what the senior author suggests is indicative of "positive selection" - evidence that this new knee gave the fledgling bipeds an evolutionary advantage. The highest functioning knees would have been selected, reducing variation in knee shape over time by decreasing the genetic variation in the switches that control the joint's formation. What variation persisted likely didn't substantially matter at that time.
"Later, as human populations expand and drift, you start getting these genetic variants that slightly modify how the knee is shaped or how the knee is maintained," explained the lead author on the paper. "Those slight deviations, acting on this constrained knee, lead to risk for developing osteoarthritis."
Those traits did not affect the success of the bipedal knee because natural selection promotes traits that allow individuals to reach sexual maturity and successfully breed. In essence, because this new knee gave young adults an edge on passing on their genetic material, it continued despite these variants. Our eventual old age had little role in its selection.
"We think that these slight modifications don't so much impact early life," said the lead. "But when you keep on walking up until you're 50 or 60, over that longer time span a super small change in your knee compounds over decades. Eventually it contributes to osteoarthritis disease in the elderly."
As a proof of principle, the authors performed two additional experiments. By studying the knee switches in patients with osteoarthritis compared to the general population, they found that osteoarthritis patients have on average more genetic variants in switches than those who don't have the disease. They also focused on a gene called GDF5 (Growth Differentiation Factor Five) that contributes to osteoarthritis risk in Europeans and Asians. Using CRISPR editing in mice and human cells, they pinpointed a genetic variant, present in billions of people, that effects the function of a key knee switch, thus changing knee shape and increasing osteoarthritis risk.
The stiffness and soreness humans feel today, therefore, may simply have piggybacked on an evolutionary advantage: the osteoarthritis came along with the knee. However, this painful feature may pay off in the study of human evolution, the researchers stress.
"The idea of tying new features with almost new diseases is a good mental framework to think of while studying these diseases of aging," said the lead author. "You can't really have your cake and eat it too."
https://www.cell.com/cell/fulltext/S0092-8674(20)30234-8
The evolution of arthritic knees
- 1,561 views
- Added
Edited
Latest News
Ancient viral DNA in the hu…
By newseditor
Posted 26 May
AI to analyze clumping prot…
By newseditor
Posted 26 May
Reversible, non-hormonal ma…
By newseditor
Posted 26 May
Dissection of the schizophr…
By newseditor
Posted 26 May
Protease action on controll…
By newseditor
Posted 25 May
Other Top Stories
Check-point inhibitors exacerbate NASH induced liver cancer
Read more
AI used to understand asbestos-linked cancer
Read more
Protein rewires cancer cell metabolism to promote metastasis
Read more
The role of hypoxia-inducible factors in tumor growth and suppression
Read more
Dual treatment to kill small cell lung cancer (SCLC) cells
Read more
Protocols
SEMORE: SEgmentation and MO…
By newseditor
Posted 26 May
Spatially resolved lipidomi…
By newseditor
Posted 24 May
Efficient expansion and CRI…
By newseditor
Posted 21 May
Massively parallel in vivo…
By newseditor
Posted 20 May
Breast cancer-on-chip for p…
By newseditor
Posted 16 May
Publications
Integrating human endogenou…
By newseditor
Posted 26 May
The thalamic reticular nucl…
By newseditor
Posted 26 May
PMI-controlled mannose meta…
By newseditor
Posted 26 May
Protein-membrane interactio…
By newseditor
Posted 26 May
Toward an interventional sc…
By newseditor
Posted 26 May
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar