Limb Lengthening Story: A Tall Order Comes True, Christy Ruhe, From 4’3″ to 4’10”

I found this story about Christy Ruhe who had achondrosplasia which made her just 4′ 3″. It is from the website limb lengtheningdoc.com which is one of the websites that is for Dr. Dror Paley. I looked a little further and found the LA Times sotry from 2004 from this link HERE.
THE NATION

Christy Ruhe was born with a form of dwarfism that left her 4-foot-3. She opted for painful, controversial surgery to grow.

February 15, 2004|  Gretchen Parker | Associated Press Writer

PICKERINGTON, Ohio — Limb-lengthening surgery is controversial among dwarfs, and it is painful. Still, many choose to undergo the bone-breaking and difficult therapy to gain inches in height. One patient who made this decision, Christy Ruhe, allowed an Associated Press reporter and photographer to closely follow her two-year progress. This is her story.

PICKERINGTON, Ohio — The tiny, silver BMW roadster slides out of the garage and zips toward the freeway. Christy Ruhe adjusts the rearview mirror and rests one hand on the steering wheel. The car, her dad’s, is a perfect fit. She looks like she’s been driving it forever.

Two years ago, she couldn’t have reached the pedals.

Christy recently finished a procedure that surgically broke her bowed legs, then stretched and straightened them, an agonizing ordeal that would leave even her questioning how much she could endure.

Once 4-foot-3, she’s now just 2 inches shy of 5 feet.

She had always craved just a few more inches. Enough to drive any car and pump her own gas, or reach the pedals under the piano. Practical things, but seven inches would accomplish so much more.

To understand why Christy would put herself through the grueling surgeries and therapy is to understand a spirit determined to be as independent as possible.

Christy was born with achondroplasia, one of 200 forms of dwarfism. Her arms grew in proportion to her torso, but her little legs were severely bowed. At 5, surgeons broke her hips and realigned them. At her sixth birthday party, she lay in a full body cast.

But the more she grew, the more stubborn her legs became — always bending outward.

Limb lengthening might help straighten her legs, her pediatric orthopedic surgeon said, but he discouraged the idea.

“His reasoning was: ‘Why would you want to put yourself through that?’ ” said her mother, Rita Ruhe (pronounced ROO-ee).

The procedure is controversial. The advocacy group Little People of America has taken an official stand against it, warning of the risks of long-term nerve and vascular damage.

But Christy, who lives in Pickerington, near Columbus, couldn’t get the idea out of her head.

Everything she did reminded her of the limitations of being 4-foot-3 in a world where most adults are at least a foot taller. She needed a footstool to wash her face at the bathroom sink or to flip a light switch. To drive a car, she needed extension pedals.

Her parents are not dwarfs; neither is her willowy older sister, Erin.

John and Rita Ruhe nurtured their daughter’s independence. But outside the Ruhe house, Christy would learn about alienation. Strangers would stare. Her legs were weak and, on walking trips, she lagged behind.

“I always felt like, why do I have to explain this? Why do I even care what they’re saying?” she said. “I did, of course. It’s impossible not to.”

At 22, Christy contacted Dr. Dror Paley and the International Center for Limb Lengthening, the clinic he co-founded with two other orthopedic surgeons at Sinai Hospital in Baltimore.

It’s now late September of 2001. Christy is focused on the changes unfolding in her own life, and the anticipation of her first limb-lengthening surgery is thrilling.

Her hospital gown drags on the floor as she slides off the bed onto a stepstool. She smiles widely at her nervous parents.

In the operating room, Paley’s plan is to break the thigh and shin bones of her left leg and stretch the bones for three or four months as they’re healing. A year later, he’ll lengthen the right leg.

Limb lengthening works by taking advantage of the body’s natural tendency to heal itself. The shin bones and femurs are broken and automatically begin to generate new bone. As they heal, they’re pulled apart to elongate them. The surgeries, which typically cost about $200,000 for both legs, are covered by insurance.

Paley cuts holes in Christy’s leg so that he can screw rods into the bone: seven in her thigh and five in her shin. Each is a foot long. Half the length protrudes from her skin, so Paley can attach them to a graphite brace that Christy will crank.

Paley bores the pins deep into the thick whiteness he sees on the X-rays.

Finding a good place to crack the bone, he first drills a tight chain of small holes. He puts a chisel to the perforation and pounds it hard with a mallet. The whirring and hammering make it sound like a construction site.

The pain is like an ocean that sucks her under again and again.

Christy lies on her stomach, and a physical therapist bends her knee as far as it will go. Muscles and nerves are stretching to meet the length of the new, soft bone.

The therapist pushes until she feels the soft tissue become elastic. It’s been only a few days since the first surgery.

Christy’s face reddens, and she rides the wave of pain with short breaths. She tries not to scream but can’t stop herself.

She wonders if the therapist knows what she’s doing. “This cannot be right!” she thinks.

(Page 2 of 2)

There’s little blood and not a lot of cutting in limb-lengthening surgery. But recovery is an extended test of mettle and will.

Christy will go through the agony twice. She knows that if she survives even the worst day, there will be another just like it a year from now.

Each day brings a monotony she comes to dread: therapy, broken up by hours of MTV and talk shows. She gets around in a wheelchair. Four times a day, she uses an Allen wrench to turn the brace and stretch her leg.

The growth of bone and muscle tissue is measured in millimeters — 1 mm a day — but Christy doesn’t feel it.

She smiles less these days, snaps at her parents and then regrets it.

She can’t sleep. The steel rods sticking out of her legs keep her from rolling over. She worries about jarring them, which sends slivers of pain up through the sore muscles.

Quitting is not an option.

“You have those moments when you say, ‘I can’t do it anymore. I can’t stand it,’ ” she said. “You have to look back at why you’re doing this. It’s for my health, my well-being.”

Before the surgeries, she talked herself into being resigned to a hard life. Now, the change in her body seems like an extraordinary gift. She reminds herself that the pain is temporary.

Gradually, she realizes how different her life will be. She even dreams differently now, seeing the world from her new height, as a person who blends into a crowd.

Most of Paley’s patients are children, and they crowd into the waiting room at the International Center for Limb Lengthening.

They come from nearly every continent. Little girls, with one shorter leg wrapped in a pink or purple cast, bring their Barbie dolls. Adult patients sit with their afflicted legs propped on a seat, rods penetrating the skin, machinery that looks misplaced inside healthy, smooth flesh.

It is spring of 2003, a year and a half after Christy’s first surgery, Her left leg, the one already lengthened, is straight and muscular. The leg is a promise to her that the surgeries will be successful.

But a chronic infection has developed in the skin around one rod in the right leg, which was operated on six months ago. Christy knows the rod must be removed.

The procedure will be done without general anesthesia, which always makes Christy’s stomach roil. The doctor expects this to be a quick procedure anyway, hardly worth administering even local anesthesia.

Paley attaches a T-shaped handle to the troubled rod. With the first turn, Christy begins to shriek. As the rod twists through bone, muscle and infected skin, she lets out short, piercing screams.

With one arm, John Ruhe tries to immobilize his daughter’s good leg and wraps his other arm around her shoulders. Her fist slams his chest as the pin turns.

Three minutes later, the end of the 12-inch pin appears. The hole in her thigh looks like a gunshot wound. Hot, red blood starts to roll out.

Christy’s back slumps. Her eyes are closed.

It’s two months later, and Christy is undergoing what she thinks will be her final surgery. The hardware that has become her second skin is to be removed.

But on an X-ray, Paley examines a hazy, white patch on the right thigh bone. Eight months of therapy should have left it solid — healed — but it isn’t.

Christy is unconscious a few feet away in the operating room when Paley makes the decision. If he takes the pins out now, the leg will break when she walks on it. They will have to wait at least two more months.

A banner at the party reads, “Congratulations Christy.”

It is a 25th birthday celebration, but the occasion also marks the end of her surgeries and crutches.

Friends and family who have supported her through an ordeal they can barely fathom write messages on a plastic sign.

“Good luck, and have a wonderful rest of your life,” says one.

“In my eyes, you’ve always been tall,” says the only note that hints at her physical transformation.

“You are my hero,” her sister writes.

All eyes are on Christy as she arrives. She steps carefully on her new legs. The right leg is still weak, but growing stronger.

Later, she says she doesn’t remember all of the pain she endured. Time has dulled the memory, and she prefers to look forward — to a life that she hopes will be easier, now that she’s in an adult-sized body.

She takes a second to place the faces before flashing her hundred-watt smile, a picture of self-assurance. “To me, I am tall,” she said. “I am a tall person now. That’s all that matters.”

Increase Height And Grow Taller Using Callus Distraction, Callotasis

Me: I wanted to go deeper into the research behind what types of surgical methods are available for limb lengthening and my searching is starting to lead me to some surgical methods I have not been aware of before. The new idea that I learned about is that of Callus Distraction, or Callotasis. It is important to realize that most forms of distraction osteogenesis operates on the callus principle. Limb Lengthening for orthopedic surgeons who specialize in the area is actually a very large area of study. There seems to be at least a dozen even more specific types of surgical methods for limb lengthening. 

The Callus method means that after you make the distraction past the peristeum (why they call it subperiosteal) and past the cortical bone (why they call it submetaphyseal) you hold the two ends close to each other and let the bones heal and create a callus. The callus that is formed gets pulled before it starts to get hard adn inelastic  from the calcium salts. Slowly more callus will develop from the distraction of the callus. You are supposed to keep the trabecular spongy bone and cavity intact. 

From source link HERE

Clin Orthop Relat Res. 1989 Apr;(241):137-45.

The callotasis method of limb lengthening.

Aldegheri R, Renzi-Brivio L, Agostini S.

Source

Center of Pediatric Orthopaedics, Institute of Clinical Orthopaedics and Traumatology, University of Verona, Italy.

Abstract

Callotasis is a lengthening technique that involves slow, controlled distraction after subperiosteal-submetaphyseal osteotomy. The technique and its advantages over other methods are described. Results of lengthenings involving 270 operated bone segments (146 femurs and 124 tibias) in 140 patients are reviewed. Ninety-five patients had limb-length inequality and 45 had hypochondroplasia or achondroplasia. On average, 6.6 cm, or 24.6% of initial length, was gained. The mean healing index was 39; the complication rate was 13.3%.

PMID:   2924457       [PubMed – indexed for MEDLINE]
Me: It appears that callotasis is a very popular approach for people who have some form of dwarfism. 
From source link HERE
J Pediatr Orthop. 1987 Mar-Apr;7(2):129-34.

Limb lengthening by callus distraction (callotasis).

De Bastiani G, Aldegheri R, Renzi-Brivio L, Trivella G.

Abstract

Callotasis is a new technique of limb lengthening involving slow distraction of the callus formed in response to a proximal submetaphyseal corticotomy. Using a dynamic axial fixator with telescoping capabilities, distraction begins after 2 weeks. When the required length is attained, the fixator is held in the rigid mode until radiographic evidence of callus is observed. The locking screw is then released, and dynamic axial loading is instituted to promote corticalization. One hundred bony segments have been lengthened; 50 patients had limb length inequality, and 23 had achondroplasia. The mean lengthening achieved was 22% (maximum, 58%). There were 14 complications (14%).

PMID:  3558791       [PubMed – indexed for MEDLINE]
From Ilizarov Jordan website
Callotasis

a distraction osteogenesis technique that involves gradual stretching of the reparative callus, which forms around bone, segments interrupted by osteotomy or nonunion fracture. The main complications of this period are axial deformity of lengthening segment, pin tract infection and fixator unstability.

From source link HERE
We can see the different ways the distraction can happen and what would happen if the distraction is done improperly at different speeds.

Rice University Engineering Students Create Automated Bone Lengthening Device And Autogenesis Device

Me: I found this article when I was searching for more information on bone lengthening. It seems that the engineering students in this generation are trying their hands and finding better ways to do limb lengthening. What makes this so interesting is that the device they have as a prototype is a combination of the efforts of students in biomedical engineering and mechanical engineering. The device does the distraction of the bones by attaching to the  wires that goes through the bone in the external fixator method and slowly moves the wires apart from each other while still keeping the overall structure stable. The unique thing they have is the feedback mechanism which makes sure the device does not overdo a distraction.

From website GizMag HERE

Students create automated bone-lengthening device

By Randolph Jonsson        April 25, 2012

Rice University's Team Break-and-Make, with their automated linear distractor

Rice University’s Team Break-and-Make, with their automated linear distractor

Whether it’s from injury, infection or malfunctioning genes, millions of children suffer from bone deformities at any given time. To help remedy the situation, doctors often resort to the painful practice of breaking the target bone and then repeatedly moving the ends apart as they attempt to grow together – a procedure known as distraction osteogenesis (DO), that has its share of risks and problems. Now, a team of undergrad students from Rice University (RU) in Texas has come up with a device they hope will make the lengthy process of bone-stretching both easier and safer for the young patients who have to endure it.

At the urging of Dr. Gloria Gogola, an orthopedic surgeon from nearby Shriners Hospital for Children in Houston, the RU team (mechanical engineering students Alvin Chou, Mario Gonzalez, Stephanie Herkes, Raquel Kahn and Elaine Wong) took on the daunting task of creating an automated linear distractor (eventually dubbed LinDi) that is both both self-adjusting and capable of monitoring and preventing potentially damaging stresses in adjacent soft tissues and nerves.

“The process of limb lengthening – essentially creating a localized mini-growth spurt – works well for bones, but is very hard on the soft tissues such as nerves and blood vessels,” Gogola said. “This team has done an outstanding job of designing a creative solution. Their device not only protects the soft tissues, it will ultimately speed up the entire process.”

With current DO rigs, long pins are embedded on both sides of the break in the bone to be lengthened. These are then attached to a bulky threaded frame outside of the appendage with a drive screw that must be regularly adjusted manually several times a day with a hex wrench. This pushes the pins further apart as the bone heals, but before it sets, allowing the gentle elongation of the bone over a period of several months. It’s a burdensome task for patient and caregiver alike.

X-ray images of various distraction osteogenesis rigs in place

X-ray images of various distraction osteogenesis rigs in place

“The problem with the current device is that there’s a lot of room for error,” RU team member Kahn said. “You can imagine that one might forget to turn it once, or turn it the wrong way, or turn it too much. And a lot of problems can arise in the soft tissue and the nerves surrounding the bone,” she added. “That’s the limiting factor of this process. But LinDi implements a motor to make the distraction process nearly continuous.”

In fact, the battery-powered LinDi self-adjusts about 1,000 times a day, which allows it to better approximate bone growth. The team’s innovative inclusion of a force-feedback sensor – a first for DO devices – monitors stress loads on surrounding tissues and shuts the system down if levels get too high, thus averting unnecessary trauma from the process.

Short-term animal testing with the help of Shriners hospital staff allowed the students to fine tune the device and confirmed that it works as planned – a nice feather in the bonnet of the soon-to-be grads and a welcome relief for the countless children and their parents who stand to benefit from this new technology in the years to come.

Me: One a related note one of the commenters made a point that there was alreday a company in the 90s which had already developed a very similar device that could automate the distraction / stretching of the bone process. However there was no feedback mechanism that told the Automator to stop when the bone is distracted too far. From the comments on the article above…

“”A friend of mine did this nearly 15 years ago while working for a company called Autogenisys they automated the Ilizarov apparatus. While they they didn’t have a feed back system you didn’t have to manually adjust it either.””

Douglas Renfro
25th April, 2012 @ 09:40 pm PDT

“”Autogenesis still exists http://autogenesisinfo.com/automator.htmlThough you cant tell from that 90s style web page if they are still in the market. I’d bet they are still the patent holder though. I wrote the software in the original Autogenesis devices. (And have no connection whatsoever to the product or current owners.)””

mclemens1969
26th April, 2012 @ 11:10 am PDT

Autogenesis Website link HERE

From the website….

The Automator

Applications:

  • Ring Frame Lengthening
  • Bone Transport
  • Unilateral Frame Lengthening
  • Joint Contracture
  • Angular Deformity Correction.

Biological Advantages:

Research indicates that frequent distractions in small increments can promote superior muscle tissue and reduce the forces required to accomplish distraction (thereby reducing pain experienced by the patient). The Automator performs precise micro-distractions every few minutes minutes rather than every six hours as is typical with manual systems. Hence, the lengthening process is more similar to the body’s natural (continuous) growth process. Additionally patients and their families report less anxiety.

BACKGROUND:

The Automator was designed to provide an improved automated alternative to manual distraction methods. The device:

  1. Costs the same or less than most manual distracters sold by large medical equipment manufacturers,
  2. Allows patients to enjoy the psychological and physical benefits of high rhythm (small increment) corrections,
  3. Allows for precision, flexibility, and reliability unavailable with manual systems, and
  4. Does not introduce installation or operational complexity to the procedure.

Automated lengthening should be the standard of care for limb lengthening and deformity correction procedures.

Product Description:

  • Continuous Distraction: The Automator  causes 1/240 mm adjustments 24 hrs per day according to the rate selected. Accuracy is maintained within 1/48 mm.
  • Compact: The self contained design involves no external cables, batteries, or programming module. Each Automator weighs approximately 6oz.
  • ProgrammableRate settings include 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, and 4.0 mm/day. The device may be set for distraction, compression, or cyclical motion (used for loading a fracture site). Rate and directional settings may be changed by the physician at any time.
  • ConvenientBrackets facilitate installation. The Automator is water resistant, and it requires minimal maintenance.
  • EfficientAutomator batteries last more than four months when lengthening at 1mm per day. The device can distract against more than 250 lbs.
  • Versatile: The device may be installed on ring or unilateral frames regardless of the distance between rings or frame components.

 

A Quick Outline Study On Progenitor Cells Condensation For Chondrocytes (IMPORTANT)

Me: The collaborator of the project at one point gave me a list of ideas and subjects we had to do more research on and one of them was cell condensation for the progenitor cells of chondrocytes. This is a quick attempt by me to go through the most basic points of cell condensation.

Note: In chondrogenesis , the condensation stage precedes the creation of the prechondroblasts, but in osteogenesis the preosteoblasts stage precedes the condensation stage. Phase a and b also contribute to chondroblast differentiation.

As stated in the first article abstract….

“”Condensations form following activation of at least three pathways:

  • 1. Initiation of epithelial-mesenchymal interactions by tenascin, BMP-2, TGF beta-1 and Msx-1 and -2.
  • 2. Up-regulation of N-CAM by activin.
  • 3. Up-regulation of fibronectin by TGF-beta, further enhancing N-CAM accumulation. (Note: Syndecan blocks fibronectin and so blocks N-CAM accumulation)

It is by these three pathways that condensations are initiated and grow.””

Extracellular matrix molecules, cell surface receptors and cell adhesion molecules, such as fibronectin, tenascin, syndecan, and N-CAM, initiate condensation formation and set condensation boundaries

So let’s try to put the entire process of cell condensation together

1. epithelial-mesenchymal interactions that precede condensation – characterized by expression of Hox genes, growth factors (TGF-beta and BMP-2) and the cell surface proteoglycan receptor, syndecan-1. versican, syndecan-3 and tenascinare present in low concentrations.

2. condensation – Expression of Msx-1 and Msx-2, growth factors and syndecan. versican, syndecan-3 and tenascin are up-regulated during condensation. Hox genes(Hoxa-2, Hoxd-13)(through indirect cell adhesion path), transcription factors(Pax-1, fibronectin, hyaluronan and hyaladherin), growth factors (activin, BMP-4 and -5, GDF-5), cell adhesion molecules (N-CAM and N-cadherin) (through direct cell adhesion path) and proteoglycans are only expressed in this phase. mRNAs for collagen types II and IX and for the core protein of cartilage proteoglycan are up-regulated. Hox genes (Hoxd-11-13) and other transcription factors (CFKH-1, MFH-1, osf-2), modulate the proliferation of cells within condensations. Subsequent growth of condensations is regulated by BMPs, which activate Pax-2, Hoxa-2 and Hoxd-11 among other genes. 

3. cell differentiation – Transcription factor Pax-1, fibronectin, hyaluronan and hyaladherin are expressed in the cell differentiation stage. Late in condensation and increasingly thereafter, the protein products of these genes (referring to all the genes in the condensation phase) accumulate aschondroblasts differentiate. Growth of a condensation ceases when Noggin inhibits BMP signalling, setting the stage for transition to the next stage of skeletal development, namely overt cell differentiation

I will try to highlight the parts which I felt are the most important.

From Source Link HERE

Int J Dev Biol. 1995 Dec;39(6):881-93.

Divide, accumulate, differentiate: cell condensation in skeletal development revisited.

Hall BK, Miyake T.

Source

Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada.

Abstract

Cell condensation is a pivotal stage in skeletal development. Although prechondrogenic condensations normally exist for some 12 h, duration can vary. Variation is seen both between condensations for different cartilages (Meckel’s vs. elastic ear cartilage) and within a single condensation from which more than one skeletal element will form, as in the three components of the single first arch chondrogenic condensation. Understanding how duration of the condensation phase is established–how the condensation phase is entered and exited during cell differentiation–remains a major area for future study. During chondrogenesis, cell-specific products such as collagen types II and IX and cartilage proteoglycan appear concomitant with condensation. Therefore, during chondrogenesis, condensation precedes commitment of cells as prechondroblasts. During osteogenesis, however, differentiation of preosteoblasts precedes condensation. Therefore, during osteogenesis, condensation amplifies the number of committed osteogenic cells. Further comparative analysis of skeletogenesis should provide us with a more rigorous understanding of cell commitment, when differentiation is initiated, how commitment and differentiation are measured and the relationship of condensation to onset of differentiation. Current knowledge of molecules characteristic of condensations focused attention on extracellular matrix and cell surface components on the one hand, and on growth factors homeobox genes and transcription factors on the other. We have drawn together the molecular data for pre-chondrogenic condensations in diagrammatic form in Figure 2. Three major phases of chondrogenesis are identified: (a) epithelial-mesenchymal interactions that precede condensation, (b) condensation itself, and (c) cell differentiation. Although we label the third phase differentiation, it is important to recognize that phases a and b also constitute aspects of chondroblast cell differentiation (see Dunlop and Hall, 1995 for a discussion of this point. The pre-condensation phase is characterized by expression of Hox genes, growth factors (TGF-beta and BMP-2) and the cell surface proteoglycan receptor, syndecan-1. Expression of Msx-1 and Msx-2, growth factors and syndecan continues into the condensation phase. Other molecules, such as versican, syndecan-3 and tenascin, present in low concentrations before condensation, are up-regulated during condensation. Yet other molecules–Hox genes, transcription factors, growth factors (activin, BMP-4 and -5, GDF-5), cell adhesion molecules and proteoglycans–are only expressed during the condensation phase, while the transcription factor Pax-1, fibronectin, hyaluronan and hyaladherin are expressed both during and after condensation. During condensation mRNAs for collagen types II and IX and for the core protein of cartilage proteoglycan are up-regulated. Late in condensation and increasingly thereafter, the protein products of these genes accumulate as chondroblasts differentiate (see Fig. 2 for details). Not all the molecules present before, during of after condensation can be placed into causal sequences. Some however can. In Figure 3 we summarize the causal sequences discussed in this paper as they relate to initiation of condensation and to transit from condensation to overt differentiation during chondrogenesis. Condensations form following activation of at least three pathways: (1) Initiation of epithelial-mesenchymal interactions by tenascin, BMP-2, TGF beta-1 and Msx-1 and -2. (2) Up-regulation of N-CAM by activin. (3) Up-regulation of fibronectin by TGF-beta, further enhancing N-CAM accumulation (Fig. 3). It is by these three pathways that condensations are initiated and grow. Transition from condensation to overt cell differentiation is under both positive and negative control (Fig. 3). Syndecan blocks fibronectin and so blocks N-CAM accumulation, preventing accumulation of additional cell

PMID: 8901191     [PubMed – indexed for MEDLINE] 
Bioessays. 2000 Feb;22(2):138-47.

All for one and one for all: condensations and the initiation of skeletal development.

Hall BK, Miyake T.

Source

Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4J1. BKH@IS.DAI.CA

Abstract

Condensation is the pivotal stage in the development of skeletal and other mesenchymal tissues. It occurs when a previously dispersed population of cells gathers together to differentiate into a single cell/tissue type such as cartilage, bone, muscle, tendon, kidney, and lung and is the earliest stage during organ formation when tissue-specific genes are upregulated. We present a synopsis of our current understanding of how condensations are initiated and grown, how their boundaries and sizes are set, how condensation ceases, and how overt differentiation begins. Extracellular matrix molecules, cell surface receptors and cell adhesion molecules, such as fibronectin, tenascin, syndecan, and N-CAM, initiate condensation formation and set condensation boundaries. Hox genes (Hoxd-11-13) and other transcription factors (CFKH-1, MFH-1, osf-2), modulate the proliferation of cells within condensations. Cell adhesion is ensured indirectly through Hox genes (Hoxa-2, Hoxd-13), and directly via cell adhesion molecules (N-CAM and N-cadherin). Subsequent growth of condensations is regulated by BMPs, which activate Pax-2, Hoxa-2 and Hoxd-11 among other genes. Growth of a condensation ceases when Noggin inhibits BMP signalling, setting the stage for transition to the next stage of skeletal development, namely overt cell differentiation. BioEssays 22:138-147, 2000.

Copyright 2000 John Wiley & Sons, Inc.

PMID: 10655033       [PubMed – indexed for MEDLINE]

Transcriptional Networks Controlling Chondrocyte Proliferation And Differentiation In Endochondral Ossification

Me: This will be a very quick note for the reader on something else to take into account when analyzing how the change between the chondrocyte proliferation and differentiation zones in the growth plates happens. The steps are tightly regulated by growth factors which activate chondrocyte specific transcription factors. They are Sox9, Gli2/3, and Runx2.
Pediatric Nephrology, April 2010, Volume 25, Issue 4, pp 625-631

Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification

  • Manuela Wuelling, Andrea Vortkamp
Abstract

During endochondral ossification bones are formed as cartilage templates in which chondrocytes proliferate, differentiate into hypertrophic chondrocytes and are gradually replaced by bone. Postnatally, remnants of embryonic chondrocytes remain in a restricted domain between the ossified regions of the bones forming the growth plate. The coordinated proliferation and differentiation of chondrocytes ensures the continuous elongation of the epiphyseal growth plates. The sequential changes between proliferation and differentiation are tightly regulated by secreted growth factors, which activate chondrocyte-specific transcription factors. Transcription factors that play critical roles in regulating cell-type-specific gene expression include Sox9, Gli2/3, and Runx2. The interaction of these transcription factors with general transcriptional regulators like histone-modifying enzymes provides an additional level of regulation to fine-tune the expression of target genes in different chondrocyte populations. This review will outline recent advances in the analysis of the complex transcriptional network that regulates the distinct steps of chondrocyte differentiation.