SYMPOSIUM: THUMB CARPOMETACARPAL ARTHRITIS
Ultrastructure and Innervation of Thumb Carpometacarpal
Ligaments in Surgical Patients With Osteoarthritis
Nathalie Mobargha MD, Cassie Ludwig BS,
Amy L. Ladd MD, Elisabet Hagert MD, PhD
? The Association of Bone and Joint Surgeons1 2013
pometacarpal (CMC-1) joint relies on musculotendinous and
ligamentous support for precise circumduction. Ligament
innervation contributes to joint stability and proprioception.
The complex configuration of the thumb car-
associated with osteoarthritis (OA) in large joints; however,
little is known about CMC-1 ligament innervation charac-
teristics in patients with OA. We studied the dorsal radial
ligament (DRL) and the anterior oblique ligament (AOL),
ligaments with a reported divergent presence of mechanore-
ceptors in nonosteoarthritic joints.
Questions/purposes This study’s purposes were (1) to
examine the ultrastructural architecture of CMC-1 liga-
ments in surgical patients with OA; (2) to describe
innervation, specifically looking at mechanoreceptors, of
these ligaments using immunohistochemical techniques
and compare the AOL and DRL in terms of innervation;
and (3) to determine whether there is a correlation between
age and mechanoreceptor density.
Methods The AOL and DRL were harvested from 11
patients with OA during trapeziectomy (10 women, one
man; mean age, 67 years). The 22 ligaments were sectioned
in paraffin and analyzed using immunoflourescent triple
ResultsIn contrast to the organized collagen bundles of
the DRL, the AOL appeared to be composed of disorga-
nized connective tissue with few collagen fibers and little
innervation. Mechanoreceptors were identified in CMC-1
ligaments of all patients with OA. The DRL was signifi-
cantly more innervated than the AOL. There was no
significant correlation between innervation of the DRL and
AOL and patient age.
ConclusionsThe dense collagen structure and rich
innervation of the DRL in patients with OA suggest that the
DRL has an important proprioceptive and stabilizing role.
Clinical Relevance Ligament innervation may correlate
with proprioceptive and neuromuscular changes in OA
pathophysiology and consequently support further investi-
gation of innervation in disease prevention and treatment
One of the authors (NM) was supported by Karolinska Institute to
cover travel expenses.
All ICMJE Conflict of Interest Forms for authors and Clinical
Orthopaedics and Related Research editors and board members are
on file with the publication and can be viewed on request.
Clinical Orthopaedics and Related Research neither advocates nor
endorses the use of any treatment, drug, or device. Readers are
encouraged to always seek additional information, including
FDA-approval status, of any drug or device prior to clinical use.
Each author certifies that his or her institution approved the human
protocol for this investigation, that all investigations were conducted
in conformity with ethical principles of research, and that informed
consent for participation in the study was obtained.
This investigation was performed at the Robert A. Chase Hand &
Upper Limb Center, Department of Orthopedic Surgery and Division
of Clinical Anatomy, Stanford University, Stanford, CA, USA.
N. Mobargha (&), E. Hagert
Department of Clinical Science and Education, Karolinska
Institute, Sjukhusbacken 10, 118 83 Stockholm, Sweden
Department of Orthopaedic Surgery, Stanford University School
of Medicine, Stanford University, Stanford, CA, USA
A. L. Ladd
Department of Orthopaedic Surgery, Robert A. Chase Hand &
Upper Limb Center, Stanford University, Stanford, CA, USA
Hand & Foot Surgery Center, Stockholm, Sweden
Clin Orthop Relat Res
and Related Research®
A Publication of The Association of Bone and Joint Surgeons®
concave-convex morphology of the thumb basal joint . It
anatomical constraints, joint stability in the normal CMC-1
joint relies on neuromuscular control: refined integration of
sensory input from muscles, ligaments, and skin.
Current evidence supports the concept of a joint as a
synovial organ: a functioning unit with both neurosensory
and neuromuscular impact on joint stability and control .
Consequently, neurosensory and neuromuscular impairment
such as inadequate reflex control of periarticular muscles,
impaired ligament function, or disturbed innervation may
contribute to osteoarthritis (OA) [27, 34, 39]. Evidence in
human and animal models [22, 36–38] supports the notion
that joint denervation may cause an increase in cartilage
degeneration, impairment of joint reflexes, and later onset or
aggravation of OA. During the process of aging, there is a
natural denervation process ; this may also contribute to
an increasing prevalence of OA with age .
The purpose of this study was to examine the ultra-
structural architecture and mechanoreceptors of CMC-1
ligaments in surgical patients with OA using immunohis-
tochemical techniques. Previous
ligaments have demonstrated a connection between liga-
mentous instability and the development of CMC-1 OA [8,
31, 32]. However, a conflict exists in the literature as to
which ligament has primary importance in CMC-1 stabil-
ity: the volar anterior oblique (AOL) or dorsoradial (DRL)
ligament. To our knowledge, no previous studies have
outlined the relationship between the DRL and CMC-1 OA
nor compared it with the AOL in surgical patients. We
studied the DRL and the AOL because these are ligaments
with the strongest mean difference in innervation density in
nonosteoarthric joints .
To investigate these issues, we proposed the following
research questions: (1) Are there histologic differences in
the cellular and structural composition of the AOL and
DRL in osteoarthritic subjects? This has been shown in
normal cadaveric dissections [16, 24, 26] but the charac-
teristics in surgical patients are unknown. (2) Are sensory
nerve endings, ie, mechanoreceptors, present in the AOL
and DRL of patients with CMC-1 OA, and, if so, is there a
difference in mechanoreceptor types between the AOL and
DRL, respectively? (3) Finally, is there a correlation
between age and mechanoreceptor density? This has been
reported in the literature in other joints [22, 36–38]. If a
similar correlation is found, it may provide insight into the
effect of age and severity progression of OA.
Materials and Methods
The AOL and DRL ligaments were harvested from the hands
of 11 patients undergoing trapeziectomy with ligament sta-
(Eaton stage 2–4) . The study cohort consisted of 10
women and one man and six right and five left hands (mean
age, 67 years; age range, 51–83 years). All surgeries and
ligament harvesting were performed by an experienced hand
surgeon (ALL) with use of 3.5 loupe magnification and
standard hand surgical instruments; ligament harvesting and
identification were performed using techniques outlined by
ligament (AOL and DRL) was harvested at the insertion into
bone at both the trapezial and metacarpal sides and suture-
marked at the distal insertion for orientation. The AOL is
located deep to the insertion of the abductor pollicis longus,
and the DRL is identified as the most radial of the dorsal
ligaments [1, 24].
Approval for this project was granted through the local
institutional review board, and the handling of human
specimens was strictly according to ethical and practical
Harvested ligaments from all 11 surgical subjects (22
specimens total) were immediately fixed in 4% formalde-
hyde, embedded in paraffin, and then sectioned at a
thickness of 5 lm before being mounted on glass slides.
The sections used for architectural analysis were stained
with Harris hematoxylin and eosin  before being
mounted under coverslips.
Two primary antibodies were used: antinerve growth factor
receptor p75 (p75) and antiprotein gene product 9.5
(PGP9.5) (Millipore, Billerica, MA, USA). Alexa Fluor
488 and 647 (Invitrogen, Carlsbad, CA, USA) were used
for the secondary antibodies. ProLong Gold Anti-Fade
(Invitrogen) was used concomitantly to highlight nuclear
material in specimens. In conjunction, triple staining with
p75, PGP9.5, and DAPI is a recently validated technique
for visualizing mechanorecptors, nerves, and arteries/arte-
rioles in contrast with collagen within ligaments .
Mobargha et al.Clinical Orthopaedics and Related Research1
a fluorescence microscope (Observer.Z1; Carl Zeiss
acquisition setting was used to analyze sensory nerve end-
ings through the use of wavelength settings of 358, 488, and
Initial scanning for orientation was performed at a wave-
of interest. Epifascicular regions that envelope the dense col-
lagen fibers were the main focus of study because nerves are
was increased tox 20 and then x 40 to investigate regions with
increased fluorescence relative to surrounding areas.
The light source was next switched to 350 nm to visu-
alize DAPI staining to differentiate between nerve bundles
in vascular structures versus in ligament tissue. If the
structure of interest was found to be nervous, fluorescence
of PGP9.5 was next visualized at 596 nm.
Lastly, similar regions were analyzed with multidi-
mensional acquisition to compare the appearance of
sensory nerve endings and evaluate for the presence of
An ordinal grading system previously used for analysis of
ligament innervation was used to quantify the degree of
innervation and to assess for mechanoreceptor presence
[15, 26]. The grading system ranged from (+++) to (?)
with (+++) representing the presence of several nerve
fascicles and mechanoreceptors, (++) representing the
presence of a single nerve fascicle and receptor, (+) rep-
resenting the presence of nerve fascicles but no receptors,
and (?) representing the presence of no nerve fibers, fas-
cicles, or mechanoreceptors.
A prestudy power analysis was not performed because the
sample size was fixed. However, a post hoc calculation
revealed that group sample sizes of 11 (number of AOL
samples) and 11 (number of DRL samples) achieve 80%
power to detect a difference of 1.79 between the null
hypothesis that both group means are 5.00 and the alter-
native hypothesis that the mean of AOL is 3.21. Therefore,
approximately 35.8% of significant differences between the
AOL and DRL would be missed using this sample
size. This post hoc calculation was done with a two-sided
two-sample t-test using known group SDs of 1.17 (DRL)
and 1.77 (AOL) and a significance level (alpha) of 0.05. A
clinically meaningful difference in innervation may be less
than 35% depending on how dramatically the difference
will prove to affect disease pathology in future studies.
A Student’s paired t-test was used to estimate the differences
in innervation grade between ligaments, obtaining two loca-
From this model, pairwise comparisons were made between
the ligaments producing p values and 95% confidence inter-
vals for the mean differences between each ligament pair.
Standard linear regression analysis was used to deter-
mine whether a linear relationship existed between mean
difference among the DRL and AOL grade innervation
scores and patient age at the time of surgery. The Pearson
correlation coefficient was used to determine the strength
of that linear relationship.
Ultrastructural Architecture of CMC-1 Ligaments
Hematoxylin and eosin staining presented reliable differ-
ences in the organization of the dorsal and volar ligaments
of live patients with CMC OA. The DRL was comprised of
organized collagen bundles with collinear orientation. The
AOL contained disorganized connective tissue with few
collagen fibers and an appearance similar to that of syno-
vial tissue (Fig. 1). These differences were consistent with
those demonstrated by a study examining dorsal and volar
ligaments of cadavers without (or in one case with mini-
mal) osteoarthritic change .
Also consistent was structural organization of both
dorsal and volar ligaments using immunofluorescence with
DAPI stain. DAPI stain revealed nuclei in the organized
collagen bundles of the DRL but revealed a lack of strong
nuclei presence in the disorganized connective of the AOL.
Identification of Mechanoreceptors
The following mechanoreceptor types were identified in
the CMC-1 ligaments of patients who underwent surgery
for CMC-OA: Ruffini endings, Pacini corpuscles, and
unclassifiable corpuscles. These were readily distinguished
from arterioles with triple staining of PGP9.5, p75, and
Osteoarthritic CMC-1 Ligaments
Immunofluorescent triple stain revealed several Ruffini
endings in the ligaments of patients who underwent surgery
for CMC OA. Ruffini endings are low-threshold, slowly
adapting mechanoreceptors more common in nonweight-
bearing joints. As previously reported in cadavers, Ruffini
endings were distinguished by their coiled dendritic end-
ings that stain independently with p75 and PGP9.5 and also
overlap, emitting yellow–orange fluorescence (Fig. 2) .
They range in size from 50 to 150 lm.
Pacini corpuscles were rarely found in the ligaments of
patients who underwent surgery for CMC OA. Pacini cor-
more common in weightbearing joints. As previously
reported in cadavers, Pacini corpuscles were identified
through their onion-like, lamellar capsule with p75 staining
and lacking PGP9.5 and DAPI immunofluorescence (Fig. 3)
The triple stain pattern was successful in distinguishing
nerves from arterioles in patients with CMC OA just as in
cadaveric specimens. p75 and PGP9.5 were found in the
adventitia and between the media and adventitia. p75 was
also found in the endothelial walls. Arterioles displayed
linear (longitudinally cut) or circular (transversely cut)
DAPI immunofluorescence (Fig. 4).
We also identified structures consistent with small, rounded
sensory nerve corpuscles in the AOL not readily classifi-
able as either Pacini or Ruffini. These small corpuscles
were labeled as unclassifiable and are being analyzed fur-
ther as to type and importance.
Distribution of Innervation
The DRL was significantly more innervated with mechano-
receptors and nerve endings than the AOL (Fig. 5).
Mechanoreceptors and nerve fibers were most readily seen
near arterioles, in the ligament epifascicular layers. A Stu-
dent’s paired t-test revealed a statistically significant
difference between innervation of the DRL (mean = 5.0455,
SD = 1.17) and AOL (mean = 2.27, SD = 1.77) of surgical
a = 0.05; 95% confidence interval, 1.513–4.033).
(t = 4.903, p = 0.001,
Age-related Differences in Mechanoreceptor Density
With the numbers available, there was no significant cor-
relation between innervation of the DRL and AOL and
patient age. The quantification of the linear relationship
between mean innervation differences in each patient’s
Fig. 1A–B Hematoxylin and eosin stain of (A) DRL and (B) AOL. The dorsal radial oblique ligament reveals organized collagen bundles with
collinear orientation. In contrast, the AOL contains disorganized connective tissue with no collagenous structure.
Mobargha et al. Clinical Orthopaedics and Related Research1
DRL and AOL and his or her age (Fig. 6) showed a
Pearson’s r of 0.557 (p = 0.075).
The CMC-1 is a complex joint with a wide ROM, pro-
viding stability in the opposite demands of both fine motor
tasks and power grasp. Since 1958, when Palmer first
revealed the mechanism of a reflex between muscles acting
on a joint and its corresponding ligaments , many
studies have proven the existence of ligamentomuscular
reflexes in the knee, ankle, shoulder, elbow, and wrist
[7, 11, 18, 33]. Afferent information from mechanorecep-
tors plays an important role in neuromuscular control and
can directly affect muscle action [18, 27, 35]. Recent
studies have suggested that ligamentous OA should be
considered its own etiology in the development of joint OA
. This new term is based on the notion that a joint is a
synovial organ in which any part of that organ such as the
cartilage, subchondral bone, synovium, ligament, nerve, or
periarticular muscle may contribute to the development of
joint OA . In other words, abnormal or impaired bio-
materials or connective tissues such as ligaments normally
stabilizing the joint may lead to changes in proprioception
and neuromuscular control and thus contribute to the
development of OA [20, 39, 46]. This form of ligamentous
OA is believed to be especially frequent in the small joints
of the hand . In CMC-1 OA, changes in ligament
structure such as increased laxity are frequent and may
Fig. 2A–D Mechanoreceptor
visualized in surgical patient with
CMC-1 OA. Ruffini ending from
a DRL stained with (A) p75
expressed on the cell membrane,
(B) PGP9.5, a pan-neuronal mar-
cytoplasm, and (C) DAPI, which
marks the nuclei of the surround-
ing fibrocytes and collagen. Triple
staining allows for visualization
of the terminal bulbous ending of
the Ruffini (arrowhead) and affer-
ent parent axon (N). (D) Areas of
overlap on immunofluorescence.
Osteoarthritic CMC-1 Ligaments
contribute to CMC-1 OA [19, 43]. In this study, we
examined the two major ligaments of CMC-1: the DRL and
AOL, and their structural and sensory properties in surgical
patients with CMC-1 OA.
In addition to the known limitations of a descriptive
study, our study is limited by the small number of subjects.
Although our population reflects the known demographic
high prevalence of CMC-1 OA in women, we would have
preferred to have analyzed an equal number of female and
male specimens. We did not include the other volar, dorsal,
and intermetacarpal ligaments [1, 21, 29] described as
important CMC-1 stabilizers. We did, however, choose the
two most surgically accessible ligaments, which have
demonstrated significant differences in structure and
innervation in normal specimens . A potential advan-
tage of our study was the use of fresh paraffin-embedded
tissue that had not previously been frozen as opposed to
fresh-frozen cadavers. Our surgical sampling allowed for
more precise analysis because there are less artifacts and
better quality of nerve endings when compared with fresh-
frozen specimens .
Our results confirm that there is a considerable structural
difference between DRL and AOL in surgical patients with
studies [16, 24, 26]. Where DRL is highly organized with
Fig. 3 Mechanoreceptor visualized in a surgical patient with CMC-1
OA. Pacinian corpuscle from a DRL triple stained with p75, PGP9.5,
and DAPI. Triple staining allows for visualization of the onion-like,
lamellar capsule of the Pacini (arrows) and afferent central axon
Fig. 4A–D Longitudinally (arrow) and transversely (A) cut arterioles
and nerves (N) visualized in a surgical patient with CMC OA.
Arterioles and nerves from a DRL stained with (A) p75 and
(B) PGP9.5 in the adventitia and between the media and adventitia.
P75 is also prominent in endothelial walls. (C) DAPI stains linear
(longitudinally cut) or circular (transversely cut) arterioles. (D) Areas
of overlap on immunofluorescence.
Mobargha et al. Clinical Orthopaedics and Related Research1
is mainly composed of loose connective tissue with sparse
nuclei. Corresponding findings have been demonstrated in
the dorsal wrist and scapholunate interosseous ligaments
[14–17, 44], where these ligaments had ample innervation
compared with volar ligaments. Our histologic observations
also add support to the theory that the DRL is a primary
stabilizer of CMC-1 [2, 3, 5, 42, 45]. In concordance with
studies made on the scapholunate interosseous ligament ,
we support the idea that intact proprioceptive mechanisms,
requiring the presence of functioning mechanoreceptors and
evolvement. In a clinical setting, this suggests the impor-
tance of early proprioceptive rehabilitation of patients with
idiopathic CMC-1 OA as well as traumatic CMC-1 injuries.
will also benefit from proprioceptive rehabilitation, a
population reported to possess decreased joint propriocep-
In addition to architectural differences, we also found
significant differences in the innervation patterns of the
AOL and DRL. Mechanoreceptors and nerve fibers were
found in both the AOL and the DRL, mostly in their
Fig. 5 Bar graph displayingsemiquantitativedistribution ofnervesand
mechanoreceptors in the dorsal radial and anterior oblique ligaments
from 11 surgical CMC OA patient specimens. The average grade score
mean for each ligament is comprised of the sum of two representative
ligament samples. For each sample, +++ (3.0) indicates richly inner-
vated with several nerve fascicles and mechanoreceptors; ++ (2.0)
indicates single nerve fascicle and mechanoreceptor; + (1.0) indicates
nerve fascicle alone; and – (0.0) indicates no signs of innervation.
Fig. 6 Linear regression analysis com-
paring the mean difference between the
DRL and AOL grade innervation scores
and patient age at the time of surgery
shows a Pearson’s r of 0.557. The data
trends toward significance with a p
value of 0.075.
Osteoarthritic CMC-1 Ligaments
epifasicular regions and close to arterioles. The Ruffini
ending was the most common mechanoreceptor found, as
has been previously observed in the wrist  and CMC-1
joint from normal cadaveric specimens. These findings
suggest that the DRL has greater proprioceptive potential
in stabilizing CMC-1 in cases with OA compared with the
AOL. Mechanoreceptors and nerve endings are more fre-
quent in the DRL than AOL. The Pacinian corpuscle, a
rapidly adapting receptor activated by changes in joint
velocity and joint compression, was an uncommon finding
in both ligaments. Subsequently, our current clinical find-
ings concur with previous cadaveric studies, which have
reported greater innervation of the dorsal deltoid ligaments,
compared with the innervation of AOL and ulnar collateral
ligaments . The abundance of nerve endings and
mechanoreceptors in the DRL may partially explain why
patients with CMC-1 OA often experience dorsal joint
We found no significant relationship between age and
innervation, although this may have been the result of
limitations of our study’s small sample size. Other studies
have suggested an age-related decrease of mechanorecep-
tors and consequently impaired proprioceptive traits
[23, 40, 44]. Previous studies have also established a
correlation between age and mechanoreceptor density
[22, 36–38]. To date, underlying pathophysiological
mechanisms of age-related changes of proprioception have
not been fully delineated. Further investigation in this area
will provide us with a better understanding of the devel-
opment of OA in the CMC-1 as well as ostheoarthritic
changes occuring in other joints.
The DRL has previously been described as the most
important ligament stabilizing CMC-1 [2, 3, 5, 42, 45] but
ours is the first study to analyze this ligament from a
proprioceptive and histological point of view. We conclude
that the DRL is a ligament with greater innervation and
thus a more significant proprioceptive role in stabilizing the
CMC-1 as compared with the AOL in patients with CMC-1
OA. In addition to its proprioceptive qualities, the DRL has
structural advantages with an increased organization of
collagen tissue, which may provide the joint with better
Although we have found the DRL to be structurally more
resilient, we cannot, based on our present data, evaluate the
condition of its proprioceptive functions or determine if its
neuromuscular control has been disrupted as a result of OA.
After joint trauma or in cases with OA, proprioceptive
disrupted and this will subsequently disable proper neuro-
muscular control. This neuromuscular disruption can leadto
disproportional joint load during certain tasks, causing pain
and weakness , which are frequent in CMC-1 OA. To
further define the proprioceptive properties, function, and
significance of the mechanoreceptors of CMC-1 in cases
with OA, studies of in vivo neuromuscular control would be
required similar to proprioceptive studies performed about
the wrist [12, 18]. Improved characterization of the inner-
vation of the CMC-1 joint on a microscopic level may
enhance current treatment options and delay progression of
study, accordingly, may provide opportunities related to
prevention and postoperative rehabilitation for patients with
CMC-1 OA as well as proprioceptive rehabilitation for
posttraumatic CMC-1 conditions.
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Osteoarthritic CMC-1 Ligaments